USP1 (1p31.3) UBP, (DUB perheen alaryhmän USP- jäsen 1

USP1 toimii monissa DNA korjausteissä 

Lähde  https://link.springer.com/article/10.1007/s12013-013-9635-3

USP1 oli niitä ensimmäisiä luonnehdittuja ubikitiinihydrolaaseja hyvin määritellyssä DDR-tiessä. Osoitettiin, että USP1 hydrolysoi selektiivisesti monoubikitiiniliitännäisiä proteiineista FANCD2 ja PCNA. FA-proteiinin FANCD2 monoubikitinoiminen oli kriittisen tärkeä tehokkaalle ICL-DNA-korjaukselle (DNA-vauriosäikeen sisäiselle korjaukselle ) .

FANCD2-proteiinin monoubikitinoiminen ei epävakauttanut proteiinia. Molemmat proteiinimuodot olivat kyllä stabiileja, mutta monoubikitinoitu FANCD2 muoto pystyi säätymään solusyklistä riippuvalla tavalla. Kun FANCD2 proteiinin saa lysiini K561 kohtaan monoubikitiininsa, se lokalisoituu uudelleen ja asettuu tuman DNA-vaurion kohtaan ja pääsee tekemään interaktion BRCA1- proteiinin ja RAD51-rekombinaasin kanssa ja FANCD2 ja BRCA2 sijoittuvat näin samaan kohtaan.

USP1- DUB havaittiin seulottaessa entsyymejä, jotka estivät ubikitiinin irrottamista FANCD2:sta

Solusykli säätelee USP1-pitoisuutta kuten FANCD2-pitoisuuttakin ja USP1:n on nähty tekevät suoraa interaktiota FANCD2:n kanssa ja lokalisoituvan samaan kohtaan kromatiinin kanssa. Huomioitava on kuitenkin, että , in vitro, eristetyn USP1-proteiinin deubikitinoiva ominaisuus ei ole voimakas. Sen sijaan on tarpeen kofaktori UAF1 (WDR48), jotta muodostuu aktiivia USP1-muotoa. UAF1 (WDR48) on WD-toiston sisältävä proteiini, joka tekee stokiometrisen kompleksin USP1- kanssa soluissa ja aktivoi esiin USP1-kompleksin katalyyttisen kyvyn. Mekanistisesti UAF1 lisää USP1 kompleksin katalyyttistä vaihtuvuutta, mutta ei lisää USP1:n affiniteettia substraattiinsa.

Tämän deubikitinaasiluokan peptidaaseilla on tavallinen säätelyllinen piirteensä: säätyminen DUB-kofaktoreilla tai substraattiin sitoutumisella.

Lisäksi on osoitettu, että USPI DUB poistaa monoubikitiinin PCNA:sta, joten se säätelee trans-leesionaalisen-DNA-synteesin (TLS) varhaisia vaiheita. TLS on prosessi, jossa spesiellit DNA-polymeraasit tekevät vaurion ohituksen translesionaalisella DNA synteesillä.

Myös interaktio UAF1 ja ELG1-proteiinien kesken rekrytoi USP1/UAF1-kompleksin monoubikitinoidulle PCNA:lle. ELG1 on proteiini, joka osallistuu replikaatiokompleksiin ja PCNA:n lataamiseen DNA:lle tehokasta replikaatiota varten; ELG1 on tunnistettu itsenäisenä tekijänä , jota tarvitaan vaimentamaan genomista instabiliteettiä.

Terminologiaa:

APC/C , Anaphase Promting Complex/Cyclosome, ( N-terminal WD40 domain stimulates catalytic activity of Apc1)

bHLH TF, basic helic loop helix transcription factor ( i.e. MYC, MYCN, HIF1A, TCF3,…)

BRCA1 (FANCS), DNA repair associated , https://www.ncbi.nlm.nih.gov/gene/?term=BRCA1

BRCA2 (FANCD1), DNA repair associated, https://www.ncbi.nlm.nih.gov/gene/675

RAD51, https://www.ncbi.nlm.nih.gov/gene/5888; DNA repair protein RAD51 homolog; BRCA1/BRCA2 containig complx, subunit 5)

CHK1 Checkpoint Kinase 1 (Kr.11q24.2) https://www.ncbi.nlm.nih.gov/gene/1111

CPT, camptothecin, a topoisomerase I inhibitor

DUB, Deubiquitinase

DSBR Double strand break repair

DDR, Damaged DNA Repair

ELG1, Enhanced level of Genomic Instability homolog 1, Chromosomal fragility associated gene 1 protein, ATAD5 , ATPase family AAA domain containig 5. (https://www.ncbi.nlm.nih.gov/gene/79915).

FANCD2, FA complementation group D2, https://en.wikipedia.org/wiki/FANCD2,

FA Fanconi Anemia

HR Homologous recombination

ICL DNA repair, DNA interstrand crosslink repair

Ku70, a key regulator of DSB repair by NHEJ.XRCC6 (Kr.22q13.2),(https://www.ncbi.nlm.nih.gov/gene/2547).

MMC, mitomycin C

NER, Nucleotide excision repair

NHEJ, Non-Homologous End Joining

PCNA Proliferating cell nuclear antigen , ATLD2 ( https://www.ncbi.nlm.nih.gov/gene/5111)

polymerase kappa, https://www.ncbi.nlm.nih.gov/protein/NP_057302.1

TLS, Translesional DNA synthesis

UAF1 (WDR48) , UASP1 Associated factor 1, (https://www.ncbi.nlm.nih.gov/gene/57599)

USP1, Ubiquitin specific proccessing protease 1, UBP, (1p31.3) (https://www.ncbi.nlm.nih.gov/gene/7398

• USP1 Functions in Multiple Repair Pathways

• The USP1 protein was one of the first ubiquitin hydrolases characterised as a key player in a well-defined DDR pathway. Thus, it was shown that USP1 selectively hydrolyses mono-ubiquitin adducts from the proteins FANCD2 and PCNA [62, 63]. Mono-ubiquitylation of the FA protein FANCD2 is critical for effective ICL DNA repair. The mono-ubiquitylation of FANCD2 does not destabilise the protein: both forms of the protein are equally stable; however, mono-ubiquitylation of FANCD2 is regulated in a cell cycle-dependent manner.
• Upon mono-ubiquitylation on lysine 561, FANCD2 re-localises to nuclear DNA-damage foci, where it interacts with BRCA1 and the RAD51 recombinase and co-localises with FANCD2 and BRCA2 [64, 65, 66]. Interestingly, USP1 was identified in a screen for enzymes that prevent the removal of ubiquitin from FANCD2 [62].
• Like mono-ubiquitylated FANCD2, USP1 levels are regulated during the cell cycle, and USP1 has also been shown to interact directly with FANCD2 and to co-localise with chromatin. Notably, however, the isolated USP1 protein does not display strong deubiquitylating activity in vitro. Instead, the co-factor, UAF1 (WDR48), is necessary to form an active USP1 enzyme. UAF1 (WDR48) is a WD40 repeat-containing protein that forms a stoichiometric complex with USP1 in cells and activates the catalytic activity of the USP1 complex [67]. Mechanistically, UAF1 increases the catalytic turnover (k _cat), but does not increase the affinity of USP1 for its substrate (K _M). Regulation of DUBs by co-factors or upon substrate binding is a common regulatory feature of that class of peptidases.
• In addition, USP1 has also been shown to remove mono-ubiquitin from PCNA, thus regulating one of the earliest steps of trans-lesion DNA synthesis (TLS)—a process in which specialised DNA polymerases synthesise DNA past a DNA lesion [63, 67].
• The USP1/UAF1 complex is also recruited to mono-ubiquitylated PCNA via an interaction between UAF1 and the protein ELG1, a protein involved in replication complexes and in loading PCNA onto DNA for efficient replication, and independently identified as a factor required to suppress genomic instability [68, 69].

Alkuhavainnot USP1:stä viittasivat siihen, että matalat USP1-pitoisuudet voisivat suojata soluja

DNA-vaurioilta. Kuitenkin jatkotutkimuksissa arvioitiin USP1:n osuus uudestaan geeni-inaktivaatiotutkimuksilla hiiressä ja osoittautui selväksi, että USP1:n - poisto johti genomiseen epävakauteen. -Kohdennettu geenideleetio hiiressä (usp1-/-) johti lisääntyneeseen perinataaliin kuolleisuuteen ja hiiriurosten infertiliteettiin, DNA-poikkisidosten hypersensitiivisyyteen ja Fankonianemiafenotyyppiin. Usp1-/- hiirialkiofibroblastit osoittivat kohonneita pitoisuuksia monoubikitinoituja FANCD2 kromatiinissa ja FANCD2:n fokaalisen koostuman virheitä ja DNA korjaustien HR puutttellisuutta. Kaksoispoistogeenisyys (Usp1/Fancd2) hiirissa osoitti korkeamman tason DDR-vikatoimintaa kuin yksittäisen Usp1:n geeninpoistotila, mikä viittaisi USP1:n omaavan DNA vauriovasteessa (DDR) muitakin tehtäviä kuin vaikutukset FANCD2:een.

Lisätukea saatiin myöhemmin USP1:n kriittisesta osasta soulun suojeluksessa DNA-vaurioilta . Tutkittiin kananpojan DT40-soluilla geenin poistoa. Siitä aiheutui solujen hypersensitiivisyyttä DNA:ta vaurioittaville aineille, mikä vahvasti puoltaa stiä mallia, että USP1 on DNA:n korjauksen positiivinen säätelijä. USP1-kompleksin irrotus DT40 -soluista johti myös lisääntyneeseen yliherkkyyteen kamptotesiiniä (camptothecin, CPT, eräs topoisomeraasi-I-inhibiittori), poly (ADP-riboosi) polymeraasi-inhibiitoreita ja DNA- poikkisidoksia aiheuttavaa agenssia mitomysiini-C: tä (MMC) kohtaan, ja lisäksi defekteihin HR korjaustiehen. Nämä muutokset voitiin palauttaa pois, jos Ku70 poistettiin ( Se on NHEJ- DNA korjaustiessä avainsäätelijä). Täten USP1- kompleksi on kriittinen ICL korjauksen ja HR korjaustien säätelijä ja yhdessä FA-tien kanssa sillä on yleensä osatehtävänä vaimentaa NHEJ- korjaustie.

• Initial observations indicated that reduced levels of USP1 would protect cells from DNA damage [62, 63]; however, follow-up studies evaluating the role of USP1 in gene inactivation studies in mice have clearly demonstrated that USP1 depletion results in genomic instability. Targeted deletion of mouse Usp1 results in elevated perinatal lethality, male infertility, DNA cross-linker hyper-sensitivity, and a FA phenotype. Usp1 ^−/− mouse embryonic fibroblasts display heightened levels of mono-ubiquitylated FANCD2 in chromatin and exhibit impaired FANCD2 focus assemblyand a defect in HR repair. Interestingly, Usp1/Fancd2 double knock-out mice display a higher level of DDR dysfunction than in the Usp1 single knock-out condition, suggesting additional DDR roles for USP1 beyond its effects on FANCD2 [70].
  
  Additional support for a critical role played by USP1 in protecting cells against DNA damage was obtained from a study in chicken DT40 cells: Usp1 disruption resulted in cellular hypersensitivity to DNA damaging agents, strongly supporting a model, whereby, USP1 is a positive regulator of DNA repair [71]. Disrupting the USP1 complex in DT40 cells also leads to increased sensitivity to camptothecin (CPT) (a topoisomerase I inhibitor), poly(ADP-ribose) polymerase inhibitors and the DNA cross-linking agent mitomycin C (MMC), together with defects in HR. These defects were largely rescued by removing Ku70, a key regulator of DSB repair by NHEJ. The USP1 complex is thus, a critical regulator of ICL repair and HR and, together with the FA pathway in general, it has a role in suppressing NHEJ [72].

Sillä aikaa kun replikaatiohaarukassa on pysähtyminen, CHK1 fosforylaatio kontrolloi G2/M- tarkistuskohtaa. Viimeaikainen näyttö viittaa siihen, että USP1 kontrolloi sitä takaisinsyöttösilmukkaa, joka rajoittaa CHK1-aktiivisuutta DNA-vauriosolujen pelastamisessa. Vaurioituneitten solujen toipumiseen osaltaan vaikuttavaa takaisinsyöttömekanismia edustanee CHK1:n - hajoituksen stimuloituminen monoubikitinoidun FANCD2:n välityksellä.

Lisäksi USP1 on tarpeen estämässä DNApolymeraasi K:n poikkeavaa rekrytoimista replikaatiohaarukkaan. Jos K-polymeraasin rekrytointi puuttuu replikaatiohaarukasta, seuraa alentunut replikaatiohaarukan nopeus ja lisääntynyt genominen instabiliteetti. Prosessia vaikuttaa USP1 ja se generoituu alkuun tuloksena PCNA:n lisääntyneestä polyubikitinoitumisesta.

Viime aikoina on myös osoitettu NER- DNA-korjausjärjestelmässä PCNA:n monoubikitinoitumista ja TLS-polymeraasin rekrytoitumista UV- vaurioihin :

NER (Nucleotide excision repair) DNA:n korjausmenetelmä voi tapahtua myös replikaatiofaasin ulkopuolella

USP1-pitoisuuksia kontrolloi proteiinitasossa APC/C .

Matalat USP1-pitoisuudet tekevät mahdolliseksi runsaat UV:n aiheuttamat PCNA-monoubikitinaatiot solusyklin G1-vaiheen aikana, mistä taas mahdollistuu TLS-polymerasien rekrytoituminen UV-leesiokohtiin.

• During replication fork stalling, the G2/M checkpoint response is controlled by CHK1 phosphorylation. Recent evidence suggests that USP1 controls a feedback loop that limits CHK1 activity to rescue DNA-damaged cells. Stimulation of CHK1 degradation by mono-ubiquitylated FANCD2 may thus, represent a feedback mechanism that contributes to the recovery of damaged cells [73]. In addition, USP1 is required to prevent aberrant recruitment of DNA polymerase Κ to replication forks. Lack of recruitment of polymerase Κ to the replication fork results in decreased replication fork speed and enhancement of genomic instability. The process is USP1 driven and generated as a result of elevated PCNA ubiquitylation [74]. PCNA mono-ubiquitylation and trans-lesion synthesis (TLS) polymerase recruitment to UV lesions have also recently been implicated in
• NER, a DNA repair mechanism that can take place outside of the replication phase [75].
• USP1 levels are controlled at the protein level by APC/C^Cdh1. Low levels of USP1 enable robust UV-induced PCNA mono-ubiquitylation during G1, which is likely to allow recruitment of TLS polymerases to UV lesions [76].

On löydetty myös eräs uusi USP1 deubikitinaatioaktiivisuus. USP1 säätelee DNA:ta sitovien proteiinien estäjiä (DI). Nämä estäjäproteiini antagonisoivat bHLH-transkriptiotekijöitä estäen differentioitumisen ja pitävät yllä kantasolutilaa. Eri kudoksissa tapahtuu näiden ID- proteiinien ubikitinoitumista ja proteosomaalista silppuroitumsita, mutta monissa neoplasmoissa nämä inhibiittorit näyttävät välttyvän hajoitukselta . Ei ole täydelleen selvitetty, onko tällä ID-proteiinien säätelyllä jotain linkkiä USP1:n tunnettuihin funktioihin DNA-vauriovasteen säätelyssä .

Samassa tutkimuksessa kirjoityajat kuitenkin pystyivät osoittamaan, että USP1 katalyyttisellä DUB-aktiivisuudellaan edisti in vitro transformaatiota ja in vivo tuumorin muodostumista, mikä edelleen tuki sitä mallia, jossa USP1 toimisi onkogeenisesti.

Yhteenvetona USP1:n avain rooleista DNA:n korjaantumisien edistämisessä voidaan sanoa näiden löytöjen valaisevan USP1:n mahdollisuutta olla kiinnostava kehiteltävien antisyöpälääkkeiden kohdemolekyyli.

• A novel function for USP1 deubiquitylating activity has recently been uncovered: USP1 regulates the stability of ID (inhibitors of DNA binding) proteins [77]. ID proteins antagonise basic-helix–loop–helix (bHLH) transcription factors to inhibit differentiation and maintain stem cell fate [78]. ID ubiquitylation and proteasomal degradation occur in differentiated tissues, but IDs appear to escape degradation in many neoplasms [79]. Whether or not the regulation of ID proteins is linked to the known functions of USP1 in regulating DNA damage responses or not remains to be fully determined. In the same study [77], the authors were able to demonstrate that USP1, through its catalytic DUB activity, promotes in vitro transformation and in vivo tumour formation, thus further supporting models in which USP1 acts as an oncogene.
  
   Taken together with its key roles in promoting DNA repair, these findings highlight the potential of USP1 as an attractive target for developing anti-cancer drugs.

Suomennosta linkissä mainitusta  lähteestä kohdasta USP1.  30.6. 2018.

DNA vauriovasteesta (DDR)

• K DNA korjausjärjestelmän  vikasäätöä voidaan hyödyntää  muuttaen tämä  syöpää edistävä  tekijä terapeuttiseksi kohteeksi. Miten sellainen on mahdollista?
• Nat Rev Cancer. 2012 Dec;12(12):801-17. doi: 10.1038/nrc3399.DNA repair dysregulation from cancer driver to therapeutic target.Curtin NJ¹ Abstract

 Terminologia:
 DDR,  DNA damage respons  DNA-vauriovaste
DNA  damage , DNA vaurio
DNA  repair pathways, DNA;n  korjaustiet 

DNA-:n vaurion korjaantumisen  ja    solusyklin tarkistuskohtiin  tulevan  signaloinnin vikasäätö  kuuluuvat  tunnettuihin  DNAvauriovasteisiin  ja assioioituvat  syöpäalttiuteen ja  vaikuttavat  antityöpäterapiavasteisiin. Yhden DNA:n korjausjärjestelmän  viallinen toiminta voi korvautua jonkin toisen  kompensoivan DDR tien funktioilla ja  tämä toinen tie voi  vahvistaa  vastettaan ja täten aiheuttaa   resistenssiä sellaista kemoterapiaa ja sädehoitoa kohtaan, jonka tarkoituksena on  vikuuttaa  syövän DNA:ta.  Tämän takia DDR-tiet  muodostavat ideaalisen  kohteen terapeuttiselle interventiolle:  ensinnäkin  estämällä  terapiaresistenssiä tai   kääntämällä resistenssin   ja toiseksi käytettäessä  jotain synteettistä syöpäsolua  tappavaa   lähestymistapaa tuhoaa spesifisesti syöpäsoluja, jotka olisivat  riippuvaisia toimivista  DNA.n korjausteistä pysyäkseen elossa  syöpään liittyvässä oksidatiivisessa  ja replikatiivisesa stressissä.
 Näitä hypoteesejä oltiin   testaamassa  2012 aikoihin  ja oltiin siirtymssä kliinseen vaiheeseen.

• Dysregulation of DNA damage repair and signalling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. Dysfunction of one DNA repair pathway may be compensated for by the function of another compensatory DDR pathway, which may be increased and contribute to resistance to DNA-damaging chemotherapy and radiotherapy. Therefore, DDR pathways make an ideal target for therapeutic intervention; first, to prevent or reverse therapy resistance; and second, using a synthetic lethal approach to specifically kill cancer cells that are dependent on a compensatory DNA repair pathway for survival in the context of cancer-associated oxidative and replicative stress. These hypotheses are currently being tested in the laboratory and are being translated into clinical studies.PMID:23175119DOI:10.1038/nrc3399 [Indexed for MEDLINE] 

• Kommenttini: Jotta  DNA vaurion korjausjärjestelmän ominaisuuksia  voidaan hyödyntää  erilaisiin terapeuttisiin strategioihin,  täytyy tietää mitä kaikkea   asiaan  sisältyy  ja tämä on laaja, globaali tieteen ala,  joka on viime vuosikymmeniä huimasti edistynyt.  Opitaan tuntemaan yhä usempia  välttämättömiä tekijöitä,  esim havaitaan uusia kehon  proteiineja, jotka osallistuvat DNA:n korjausjärjestelmään. Myös syöville tyypillisiä genomisia ilmiöitä ollaan kartoitettu ja kartoittamassa.  Näyttää siltä, että  uudet löydöt ilmenevät melko pian  myös internetissä ja  siellä on maailman suurilla yleiskielillä saatavissa paljon  tietoa.  Nyt  katselen jatkossa jonkin aikaa  artikkelia.  On  monien vuosien viive, ennen kuin tieto tulee tiedemiestasolta yleistiedoksi, Yleensä kyse on vuosikymmenien viiveestä.  Tieteellisen tiedon puoliintumisajaksikin on sanottu  viittä vuotta, joten  aiemmin  valmistuneet akateemikot joutuvat jatkuvasti pävittämään tietämystään huikean nopean  biologisten tieteiden kehityksen ja teknisten havaintokeinojen   kohentumisen  takia. Vähintä nyt on akateemikoille, että hankkii  uudistuvaa valmista  tietoa, jotta voi  sitten  välittää  yleistiedoksi.    
  
  https://link.springer.com/article/10.1007/s12013-013-9635-3
•  
  
  Cell Biochemistry and Biophysics
  

  September 2013, Volume 67, Issue 1, pp 25–43 | Cite as

  Deubiquitylating Enzymes and DNA Damage Response Pathways

  Sana
  Deubiquitination  ( löytyi vain englanniksi)
  
  Sana
  Ubiquitination
  

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COPS5 (8q13.1) , CSN5, JAB1, MOV-34, SGN5 . COPS5 on yksi COP9 -signalosomin alayksiköistä. DUB JAMM

COPS5 (8q13.1)

https://www.ncbi.nlm.nih.gov/gene

Also known as

CSN5; JAB1; SGN5; MOV-34

Summary

The protein encoded by this gene is one of the eight subunits of COP9 signalosome, a highly conserved protein complex that functions as an important regulator in multiple signaling pathways. The structure and function of COP9 signalosome is similar to that of the 19S regulatory particle of 26S proteasome. COP9 signalosome has been shown to interact with SCF-type E3 ubiquitin ligases and act as a positive regulator of E3 ubiquitin ligases. This protein is reported to be involved in the degradation of cyclin-dependent kinase inhibitor CDKN1B/p27Kip1. It is also known to be an coactivator that increases the specificity of JUN/AP1 transcription factors. [provided by RefSeq, Jul 2008]

Expression

Ubiquitous expression in testis (RPKM 37.3), heart (RPKM 32.6) and 25 other tissues See more

1. CSN5/JAB1 suppresses the WNT inhibitor DKK1 in colorectal cancer cells. Jumpertz S, et al. Cell Signal, 2017 Jun. PMID 28229932
2. Oxidized LDL-induced JAB1 influences NF-κB independent inflammatory signaling in human macrophages during foam cell formation. Schwarz A, et al. J Biomed Sci, 2017 Feb 7. PMID 28173800, Free PMC Article
3. Jab1 promotes glioma cell proliferation by regulating Siah1/β-catenin pathway. Zhu Y, et al. J Neurooncol, 2017 Jan. PMID 27640199
4. JAB1 accelerates odontogenic differentiation of dental pulp stem cells. Lian M, et al. J Mol Histol, 2016 Jun. PMID 26989054
5. Suppression of CSN5 promotes the apoptosis of gastric cancer cells through regulating p53-related apoptotic pathways. Sang MM, et al. Bioorg Med Chem Lett, 2015 Aug 1. PMID 26048783

  https://www.ncbi.nlm.nih.gov/pubmed/19576224

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. We identified a novel Jab1-Trx axis that is a key cellular process in the pathobiologic characteristics of acute myeloid leukemia (AML-M5). Targeting the ROS/Jab1/Trx pathway could be beneficial in the treatment of AML-M5
2. These data identified CSN5 as a critical oncoprotein involved in progression of hepatocellular carcinoma (HCC) cells, which could serve as a potential therapeutic target in HCC patients.
3. The authors find that UCHL3 regulates COPS5-dependent deneddylation of Cullin1, which is an essential component of SCF(beta-TrCP) complex and associated with SCF(beta-TrCP) activities. The authors further demonstrate that UCHL3 upregulates the levels of SCF(beta-TrCP) substrates including IFN-I receptor IFNAR1, which enhances IFN-I mediated signaling pathway and antiviral activity.
4. Collectively, our findings suggest that JAB1 activates the neuronal differentiation ability of CPNE1 through the binding of C2A domain in CPNE1 with MPN domain in JAB1.
5. data suggests that Jab1-mediated phosphorylation of p53 at Thr155 residue mediates nuclear export of p53
6. CSN5 is contributed to colorectal cancer development by actively driving aberrant WNT signaling through repression of the WNT antagonist DKK1.
7. The results of this study suggest that Jab1 promotes glioma cell proliferation and increased expression of Jab1 in glioma patients may amplify beta-catenin signaling to contribute to glioma cell proliferation.
8. Furthermore, inhibition of COPS5 resulted in an elevation of Akt expression and sensitized SOC cells to Akt inhibitor MK2206. Suppression of COPS5 and Akt offers a potential strategy for the treatment of SOC.
9. The data identified CSN5 as a critical oncoprotein involved in migration and invasion of RCC cells, which could serve as a potential therapeutic target in RCC patients.
10. High JAB1 expression is associated with nasopharyngeal cancer.

Kruppelin kaltaiset sinkkipitoiset tekijät fylogeneettisesti

https://en.wikipedia.org/wiki/Kruppel-like_factors

 https://upload.wikimedia.org/wikipedia/en/1/1c/KLFs_function_and_properties_2.png

ATXN3L (Xp22.2) MJDL

Tämän geenin koodamaa deubkitinaasi on   kemiallisesti testattuna teholtaan voimakkaampi kuin ATX3 geenin deubikitinaasi (ATXN3) verrattuna synteettiseen valmisteeseen. Näyttää siltä että tiedemiehet  oat  varuillaan tämän proteiinin ja geenin suhteen, koska seuraava  tieto on esiinseulottuna 2015. Se näyttää deubikitinoivan  tärkeän  tekijän  " Krüppel-like factor 5". KLF5 


KLF5 kuuluu laajan  ZNF proteiinijoukon suurimpaan  ryhmään : niiden  tunnus on Znf C2H2- tyyppisesti koordinoitunut sinkki ( ZNF onryhmänimi).
 Näitä  ZNF-geenejä on  720 ja niistä  on 372,  jotka ovat transkriptiotekijäitä.

 https://www.ncbi.nlm.nih.gov/gene/92552

ATXN3L  

Also known as

MJDL

Summary

This intronless gene may be a pseudogene (PMID:11450850). This gene is similar to the multi-exon gene which encodes ataxin 3 and contains a coding region which could encode a protein similar to ataxin 3. Mutations in the gene encoding ataxin 3 are associated with Machado-Joseph disease. [provided by RefSeq, Sep 2011]

Preferred Names

ataxin-3-like protein

Names

machado-Joseph disease protein 1-like

putative ataxin-3-like protein

ataxin-3-like protein [Homo sapiens]

NCBI Reference Sequence: NP_001129467.1

Identical Proteins FASTA Graphics

Go to:

LOCUS       NP_001129467             355 aa            linear   PRI 24-JUN-2018
DEFINITION  ataxin-3-like protein [Homo sapiens].
ACCESSION   NP_001129467 XP_045705 XP_947648
VERSION     NP_001129467.1
DBSOURCE    REFSEQ: accession NM_001135995.1
KEYWORDS    RefSeq.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (residues 1 to 355)
  AUTHORS   Ge F, Chen W, Qin J, Zhou Z, Liu R, Liu L, Tan J, Zou T, Li H, Ren
            G and Chen C.
  TITLE     Ataxin-3 like (ATXN3L), a member of the Josephin family of
            deubiquitinating enzymes, promotes breast cancer proliferation by
            deubiquitinating Kruppel-like factor 5 (KLF5)
  JOURNAL   Oncotarget 6 (25), 21369-21378 (2015)
   PUBMED   26079537
  REMARK    GeneRIF: ATXN3L has a role in the regulation of KLF5 stability in
            breast cancer
REFERENCE   2  (residues 1 to 355)
  AUTHORS   Weeks SD, Grasty KC, Hernandez-Cuebas L and Loll PJ.
  TITLE     Crystal structure of a Josephin-ubiquitin complex: evolutionary
            restraints on ataxin-3 deubiquitinating activity
  JOURNAL   J. Biol. Chem. 286 (6), 4555-4565 (2011)
   PUBMED   21118805
REFERENCE   3  (residues 1 to 355)
  AUTHORS   Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D,
            Platzer M, Howell GR, Burrows C, Bird CP, Frankish A, Lovell FL,
            Howe KL, Ashurst JL, Fulton RS, Sudbrak R, Wen G, Jones MC, Hurles
            ME, Andrews TD, Scott CE, Searle S, Ramser J, Whittaker A, Deadman
            R, Carter NP, Hunt SE, Chen R, Cree A, Gunaratne P, Havlak P,
            Hodgson A, Metzker ML, Richards S, Scott G, Steffen D, Sodergren E,
            Wheeler DA, Worley KC, Ainscough R, Ambrose KD, Ansari-Lari MA,
            Aradhya S, Ashwell RI, Babbage AK, Bagguley CL, Ballabio A,
            Banerjee R, Barker GE, Barlow KF, Barrett IP, Bates KN, Beare DM,
            Beasley H, Beasley O, Beck A, Bethel G, Blechschmidt K, Brady N,
            Bray-Allen S, Bridgeman AM, Brown AJ, Brown MJ, Bonnin D, Bruford
            EA, Buhay C, Burch P, Burford D, Burgess J, Burrill W, Burton J,
            Bye JM, Carder C, Carrel L, Chako J, Chapman JC, Chavez D, Chen E,
            Chen G, Chen Y, Chen Z, Chinault C, Ciccodicola A, Clark SY, Clarke
            G, Clee CM, Clegg S, Clerc-Blankenburg K, Clifford K, Cobley V,
            Cole CG, Conquer JS, Corby N, Connor RE, David R, Davies J, Davis
            C, Davis J, Delgado O, Deshazo D, Dhami P, Ding Y, Dinh H,
            Dodsworth S, Draper H, Dugan-Rocha S, Dunham A, Dunn M, Durbin KJ,
            Dutta I, Eades T, Ellwood M, Emery-Cohen A, Errington H, Evans KL,
            Faulkner L, Francis F, Frankland J, Fraser AE, Galgoczy P, Gilbert
            J, Gill R, Glockner G, Gregory SG, Gribble S, Griffiths C, Grocock
            R, Gu Y, Gwilliam R, Hamilton C, Hart EA, Hawes A, Heath PD,
            Heitmann K, Hennig S, Hernandez J, Hinzmann B, Ho S, Hoffs M,
            Howden PJ, Huckle EJ, Hume J, Hunt PJ, Hunt AR, Isherwood J, Jacob
            L, Johnson D, Jones S, de Jong PJ, Joseph SS, Keenan S, Kelly S,
            Kershaw JK, Khan Z, Kioschis P, Klages S, Knights AJ, Kosiura A,
            Kovar-Smith C, Laird GK, Langford C, Lawlor S, Leversha M, Lewis L,
            Liu W, Lloyd C, Lloyd DM, Loulseged H, Loveland JE, Lovell JD,
            Lozado R, Lu J, Lyne R, Ma J, Maheshwari M, Matthews LH, McDowall
            J, McLaren S, McMurray A, Meidl P, Meitinger T, Milne S, Miner G,
            Mistry SL, Morgan M, Morris S, Muller I, Mullikin JC, Nguyen N,
            Nordsiek G, Nyakatura G, O'Dell CN, Okwuonu G, Palmer S, Pandian R,
            Parker D, Parrish J, Pasternak S, Patel D, Pearce AV, Pearson DM,
            Pelan SE, Perez L, Porter KM, Ramsey Y, Reichwald K, Rhodes S,
            Ridler KA, Schlessinger D, Schueler MG, Sehra HK, Shaw-Smith C,
            Shen H, Sheridan EM, Shownkeen R, Skuce CD, Smith ML, Sotheran EC,
            Steingruber HE, Steward CA, Storey R, Swann RM, Swarbreck D, Tabor
            PE, Taudien S, Taylor T, Teague B, Thomas K, Thorpe A, Timms K,
            Tracey A, Trevanion S, Tromans AC, d'Urso M, Verduzco D, Villasana
            D, Waldron L, Wall M, Wang Q, Warren J, Warry GL, Wei X, West A,
            Whitehead SL, Whiteley MN, Wilkinson JE, Willey DL, Williams G,
            Williams L, Williamson A, Williamson H, Wilming L, Woodmansey RL,
            Wray PW, Yen J, Zhang J, Zhou J, Zoghbi H, Zorilla S, Buck D,
            Reinhardt R, Poustka A, Rosenthal A, Lehrach H, Meindl A, Minx PJ,
            Hillier LW, Willard HF, Wilson RK, Waterston RH, Rice CM, Vaudin M,
            Coulson A, Nelson DL, Weinstock G, Sulston JE, Durbin R, Hubbard T,
            Gibbs RA, Beck S, Rogers J and Bentley DR.
  TITLE     The DNA sequence of the human X chromosome
  JOURNAL   Nature 434 (7031), 325-337 (2005)
   PUBMED   15772651
REFERENCE   4  (residues 1 to 355)
  AUTHORS   Ichikawa Y, Goto J, Hattori M, Toyoda A, Ishii K, Jeong SY, Hashida
            H, Masuda N, Ogata K, Kasai F, Hirai M, Maciel P, Rouleau GA,
            Sakaki Y and Kanazawa I.
  TITLE     The genomic structure and expression of MJD, the Machado-Joseph
            disease gene
  JOURNAL   J. Hum. Genet. 46 (7), 413-422 (2001)
   PUBMED   11450850
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from AK302365.1, BC137186.1,
            DB540973.1 and AB050195.1.
            This sequence is a reference standard in the RefSeqGene project.
            
            Summary: This intronless gene may be a pseudogene (PMID:11450850).
            This gene is similar to the multi-exon gene which encodes ataxin 3
            and contains a coding region which could encode a protein similar
            to ataxin 3. Mutations in the gene encoding ataxin 3 are associated
            with Machado-Joseph disease. [provided by RefSeq, Sep 2011].
FEATURES             Location/Qualifiers
     source          1..355
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="X"
                     /map="Xp22.2"
     Protein         1..355
                     /product="ataxin-3-like protein"
                     /EC_number="3.4.19.12"
                     /note="putative ataxin-3-like protein; machado-Joseph
                     disease protein 1-like"
                     /calculated_mol_wt=40616
     Region          9..163
                     /region_name="Josephin"
                     /note="Josephin; pfam02099"
                     /db_xref="CDD:280299"
     Region          262..323
                     /region_name="SUIM_assoc"
                     /note="Unstructured region C-term to UIM in Ataxin3;
                     pfam16619"
                     /db_xref="CDD:293225"
     CDS             1..355
                     /gene="ATXN3L"
                     /gene_synonym="MJDL"
                     /coded_by="NM_001135995.1:466..1533"
                     /db_xref="CCDS:CCDS48080.1"
                     /db_xref="GeneID:92552"
                     /db_xref="HGNC:HGNC:24173"
                     /db_xref="MIM:300920"
ORIGIN      
        1 mdfifhekqe gflcaqhcln nllqgeyfsp velasiahql deeermrmae ggvtseeyla
       61 flqqpsenmd dtgffsiqvi snalkfwgle iihfnnpeyq klgidpiner sficnykqhw
      121 ftirkfgkhw fnlnsllagp elisdtclan flarlqqqay svfvvkgdlp dceadqllqi
      181 isveemdtpk lngkklvkqk ehrvyktvle kvseesdesg tsdqdeedfq ralelsrqet
      241 nredehlrst ielsmqgssg ntsqdlpkts cvtpaseqpk kikedyfekh qqeqkqqqqq
      301 sdlpghssyl herpttssra iesdlsddis egtvqaavdt ileimrknlk ikgek
//

 

ATX3 (14q32.12), JOS, KJD1, SCA3, MHD, AT3

ATX3 toimii deubikitinaasina Chk1:n stabiloimisessa   pidentyneen replikatorisen stressin aikana- Tämä on havaittu  2017.

• https://www.ncbi.nlm.nih.gov/pubmed/28180282

The Chk1 protein is essential for genome integrity maintenance and cell survival in eukaryotic cells.
After prolonged replication stress, Chk1 can be targeted for proteasomal degradation to terminate checkpoint signaling after DNA repair finishes.

 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569015/bin/nihms720037f3.jpg


To ensure proper activation of DNA damage checkpoint and DNA repair signaling, a steady-state level of Chk1 needs to be retained under physiological conditions. Here, we report a dynamic signaling pathway that tightly regulates Chk1 stability. Under unperturbed conditions and upon DNA damage, ataxin-3 (ATX3) interacts with Chk1 and protects it from DDB1/CUL4A- and FBXO6/CUL1-mediated polyubiquitination and subsequent degradation, thereby promoting DNA repair and checkpoint signaling. Under prolonged replication stress, ATX3 dissociates from Chk1, concomitant with a stronger binding between Chk1 and its E3 ligase, which causes Chk1 proteasomal degradation. ATX3 deficiency results in pronounced reduction of Chk1 abundance, compromised DNA damage response, G2/M checkpoint defect and decreased cell survival after replication stress, which can all be rescued by ectopic expression of ATX3. Taken together, these findings reveal ATX3 to be a novel deubiquitinase of Chk1, providing a new mechanism of Chk1 stabilization in genome integrity maintenance.

• ATX3 is DUB for ERAD machinery    p97complex,  and transiently  also for derlin-VIMP-complex.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064388/

J Cell Biol. 2006 Sep 25; 174(7): 963–971.

doi:  10.1083/jcb.200605100

PMCID: PMC2064388

PMID: 17000876

Article

Regulation of retrotranslocation by p97-associated deubiquitinating enzyme ataxin-3

ATX3 toimii  deubikitinaasina tärkeille ERAD- komplekseille.

• https://www.ncbi.nlm.nih.gov/pubmed/28939772

PubMed  GENE - Knowledge about   of   mutations of this gene  (spinocerebellar ataxia types  , caused by  polyglutamine extensions in Ataxin- C-terminal.  Proteolytic cleavage   makes  neurotoxic fractions.)   

https://www.ncbi.nlm.nih.gov/gene/4287

JOSD2 (19q13.33) Josephin Domain 2,

josephin-2 isoform 1 [Homo sapiens]

NCBI Reference Sequence: NP_001257568.1

Identical Proteins FASTA Graphics

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LOCUS       NP_001257568             188 aa            linear   PRI 25-JUN-2018
DEFINITION  josephin-2 isoform 1 [Homo sapiens].
ACCESSION   NP_001257568
VERSION     NP_001257568.1
DBSOURCE    REFSEQ: accession NM_001270639.1
KEYWORDS    RefSeq.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (residues 1 to 188)
  AUTHORS   Weeks SD, Grasty KC, Hernandez-Cuebas L and Loll PJ.
  TITLE     Crystal structure of a Josephin-ubiquitin complex: evolutionary
            restraints on ataxin-3 deubiquitinating activity
  JOURNAL   J. Biol. Chem. 286 (6), 4555-4565 (2011)
   PUBMED   21118805
REFERENCE   2  (residues 1 to 188)
  AUTHORS   Tzvetkov N and Breuer P.
  TITLE     Josephin domain-containing proteins from a variety of species are
            active de-ubiquitination enzymes
  JOURNAL   Biol. Chem. 388 (9), 973-978 (2007)
   PUBMED   17696782
REFERENCE   3  (residues 1 to 188)
  AUTHORS   Baek KH.
  TITLE     Cytokine-regulated protein degradation by the ubiquitination system
  JOURNAL   Curr. Protein Pept. Sci. 7 (2), 171-177 (2006)
   PUBMED   16611142
  REMARK    Review article
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from HY056543.1, BC062416.1 and
            BM970016.1.
            
            Summary: This gene encodes a protein containing a Josephin domain.
            Josephin domain-containing proteins are deubiquitinating enzymes
            which catalyze the hydrolysis of the bond between the C-terminal
            glycine of the ubiquitin peptide and protein substrates.
            Alternatively spliced transcript variants encoding multiple
            isoforms have been observed for this gene. [provided by RefSeq, Jul
            2012].
            
            Transcript Variant: This variant (1) represents the longest
            transcript and encodes the longer isoform (1). Variants 1, 2, 4 and
            5 encode the same isoform (1).
            
            ##Evidence-Data-START##
            Transcript exon combination :: SRR1163655.429197.1,
                                           ERR279846.11375.1 [ECO:0000332]
            RNAseq introns              :: single sample supports all introns
                                           SAMN03267761, SAMN03267763
                                           [ECO:0000348]
            ##Evidence-Data-END##
FEATURES             Location/Qualifiers
     source          1..188
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="19"
                     /map="19q13.33"
     Protein         1..188
                     /product="josephin-2 isoform 1"
                     /EC_number="3.4.19.12"
                     /note="josephin-2; josephin domain-containing protein 2"
                     /calculated_mol_wt=20625
     Region          23..166
                     /region_name="Josephin"
                     /note="Josephin; pfam02099"
                     /db_xref="CDD:307972"
     CDS             1..188
                     /gene="JOSD2"
                     /gene_synonym="SBBI54"
                     /coded_by="NM_001270639.1:257..823"
                     /note="isoform 1 is encoded by transcript variant 1"
                     /db_xref="CCDS:CCDS12797.1"
                     /db_xref="GeneID:126119"
                     /db_xref="HGNC:HGNC:28853"
                     /db_xref="MIM:615324"
ORIGIN      
        1 msqapgaqps pptvyherqr lelcavhaln nvlqqqlfsq eaadeickrl apdsrlnphr
       61 sllgtgnydv nvimaalqgl glaavwwdrr rplsqlalpq vlglilnlps pvslgllslp
      121 lrrrhwvalr qvdgvyynld sklrapealg dedgvrafla aalaqglcev llvvtkevee
      181 kgswlrtd
//

JOSD1 (22q13.1),dj508I15.2 (DUB alaruhmästä MJD)

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LOCUS       NP_001347164             202 aa            linear   PRI 15-JUN-2018
DEFINITION  josephin-1 [Homo sapiens].
ACCESSION   NP_001347164 XP_005261936
VERSION     NP_001347164.1
DBSOURCE    REFSEQ: accession NM_001360235.1
KEYWORDS    RefSeq.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (residues 1 to 202)
  AUTHORS   Wang X, Zhang L, Zhang Y, Zhao P, Qian L, Yuan Y, Liu J, Cheng Q,
            Xu W, Zuo Y, Guo T, Yu Z and Zheng H.
  TITLE     JOSD1 Negatively Regulates Type-I Interferon Antiviral Activity by
            Deubiquitinating and Stabilizing SOCS1
  JOURNAL   Viral Immunol. 30 (5), 342-349 (2017)
   PUBMED   28355105
  REMARK    GeneRIF: In this study, the authors report that JOSD1 plays an
            important role in regulating type-I interferon (IFN-I)-mediated
            antiviral activity. JOSD1 physically interacts with SOCS1, which is
            an essential negative regulator of many cytokines signaling, and
            enhances SOCS1 stability by deubiquitinating K48-linked
            polyubiquitination of SOCS1.
REFERENCE   2  (residues 1 to 202)
  AUTHORS   Yu H, Tardivo L, Tam S, Weiner E, Gebreab F, Fan C, Svrzikapa N,
            Hirozane-Kishikawa T, Rietman E, Yang X, Sahalie J, Salehi-Ashtiani
            K, Hao T, Cusick ME, Hill DE, Roth FP, Braun P and Vidal M.
  TITLE     Next-generation sequencing to generate interactome datasets
  JOURNAL   Nat. Methods 8 (6), 478-480 (2011)
   PUBMED   21516116
REFERENCE   3  (residues 1 to 202)
  AUTHORS   Ghosh D, Lippert D, Krokhin O, Cortens JP and Wilkins JA.
  TITLE     Defining the membrane proteome of NK cells
  JOURNAL   J Mass Spectrom 45 (1), 1-25 (2010)
   PUBMED   19946888
REFERENCE   4  (residues 1 to 202)
  AUTHORS   Sakai N, Terami H, Suzuki S, Haga M, Nomoto K, Tsuchida N,
            Morohashi K, Saito N, Asada M, Hashimoto M, Harada D, Asahara H,
            Ishikawa T, Shimada F and Sakurada K.
  TITLE     Identification of NR5A1 (SF-1/AD4BP) gene expression modulators by
            large-scale gain and loss of function studies
(The NR5A1 gene provides instructions for producing a transcription factor called the steroidogenic factor 1. A transcription factor is a protein that attaches (binds) to specific regions of DNA and helps control the activity of particular genes. Steroidogenic factor 1 helps control the activity of several genes related to the development of the gonads (ovaries and testes) and the adrenal glands, which are small glands located on top of each kidney. )
  JOURNAL   J. Endocrinol. 198 (3), 489-497 (2008)
   PUBMED   18579725
  REMARK    GeneRIF: The gain of function studies indicated that Josephin
            domain containing 1 activate NR5A1 gene expression.
REFERENCE   5  (residues 1 to 202)
  AUTHORS   Albrecht M, Hoffmann D, Evert BO, Schmitt I, Wullner U and Lengauer
            T.
  TITLE     Structural modeling of ataxin-3 reveals distant homology to
            adaptins
  JOURNAL   Proteins 50 (2), 355-370 (2003)
   PUBMED   12486728
REFERENCE   6  (residues 1 to 202)
  AUTHORS   Dunham I, Shimizu N, Roe BA, Chissoe S, Hunt AR, Collins JE,
            Bruskiewich R, Beare DM, Clamp M, Smink LJ, Ainscough R, Almeida
            JP, Babbage A, Bagguley C, Bailey J, Barlow K, Bates KN, Beasley O,
            Bird CP, Blakey S, Bridgeman AM, Buck D, Burgess J, Burrill WD,
            O'Brien KP et al.
  TITLE     The DNA sequence of human chromosome 22
  JOURNAL   Nature 402 (6761), 489-495 (1999)
   PUBMED   10591208
  REMARK    Erratum:[Nature 2000 Apr 20;404(6780):904]
COMMENT     VALIDATED REFSEQ: This record has undergone validation or
            preliminary review. The reference sequence was derived from
            DB064998.1, HY026936.1, BC015026.3 and CA449010.1.
            On Jan 29, 2018 this sequence version replaced XP_005261936.1.
            
            Transcript Variant: This variant (2) contains a different 5'
            non-coding exon compared to variant 1. Variants 1, 2, and 3 encode
            the same protein.
            
            ##Evidence-Data-START##
            CDS exon combination :: SRR1660803.252891.1, SRR1803613.281012.1
                                    [ECO:0000331]
            RNAseq introns       :: single sample supports all introns
                                    SAMEA1970526, SAMEA2145774 [ECO:0000348]
            ##Evidence-Data-END##
FEATURES             Location/Qualifiers
     source          1..202
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="22"
                     /map="22q13.1"
     Protein         1..202
                     /product="josephin-1"
                     /EC_number="3.4.19.12"
                     /note="josephin domain-containing 1; josephin
                     domain-containing protein 1"
                     /calculated_mol_wt=23067
     Site            15
                     /site_type="phosphorylation"
                     /experiment="experimental evidence, no additional details
                     recorded"
                     /note="Phosphoserine. {ECO:0000244|PubMed:23186163};
                     propagated from UniProtKB/Swiss-Prot (Q15040.1)"
     Region          35..173
                     /region_name="Josephin"
                     /note="Josephin; pfam02099"
                     /db_xref="CDD:307972"
     CDS             1..202
                     /gene="JOSD1"
                     /gene_synonym="dJ508I15.2"
                     /coded_by="NM_001360235.1:794..1402"
                     /db_xref="CCDS:CCDS13976.1"
                     /db_xref="GeneID:9929"
                     /db_xref="HGNC:HGNC:28953"
                     /db_xref="MIM:615323"
ORIGIN      
        1 mscvpwkgdk akseslelpq aappqiyhek qrrelcalha lnnvfqdsna ftrdtlqeif
       61 qrlspntmvt phkksmlgng nydvnvimaa lqtkgyeavw wdkrrdvgvi altnvmgfim
      121 nlpsslcwgp lklplkrqhw icvrevggay ynldsklkmp ewiggeselr kflkhhlrgk
      181 ncelllvvpe eveahqswrt dv
//

OTUD4 (4q31.12) DUBA6, HSHIN1, HIN1

OTUD4 (4q31.21)

Vaihtoehtoisesti silmukoituneita transkriptivariantteja löydetään tästä geenistä. Tätä lyhyttä proteiini-isoformia on havaittavissa vain HIV-1 retroviruksella infektoituneissa soluissa. Geenillä on synonyyminimiä HIN1, DUBA6, HSHIN1. Jo vuonna 1992 tutkijat tekivät havainnon proteiinista, jota muodostui vain HIV1 viruksella infektoituneista soluista. (”HIV-1 promotor insertion revealed by selective detection of chimeric provirus-host-gene transcripts). Pitemmässä variantissa on 1049 aminohappoa. Vaihtoehtoisnimi proteiinille on HIV-1 viruksen indusoima proteiini HIN-1. Suositeltu nimi on  OTU-domeenin sisältävä proteiini 4. OTUD4 pidetään  varsinaisesti  K48 deubikitinaasina, mutta fosfoaktivoitu OTUD4  paljastaa sen latentin   K63-deubikitinaasipiirteen, joka säätelee MyD88:sta riippuvaa järjestelmää. (MyD99 proteiini on tärkeänä adaptorina järjestelmässä, joka tunnistaa soluun tulevia patogeenejä Tollin reseptoreilla). https://www.researchgate.net/figure/Signal-transduction-downstream-of-MYD88-dependent-and-independent-pathways-Activation-of_fig1_264866332.

OTUD4 osallistuu DNA:n alkylaatiovaurion korjaukseen toimimalla alustana tai rekrytoijana toisille DUB-perheen jäsenille ( USP7/HAUSP ja USP9X), jotka edistävät DNA:n alkylaatiovauriota korjaavien demetylaasien (hAlkBH2 ja hAlkBH3) dealkyloivia toimia - kun ne irrottavat DNA:n puriinista N1-asemaN ALKYYLIÄ  tai pyrimidiinistä N3 - aseman alkyylia. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475402/

(Laajemman käsityksen DNA:n korjaukseen osllistuvista DUB- entsyymeistä saa Springerlinkistä. 

https://link.springer.com/article/10.1007/s12013-013-9635-3 )

PubMed tietoa  OTUD GEENISTÄ (4q31.12)

• https://www.ncbi.nlm.nih.gov/gene/54726 
• Also known as HIN1; DUBA6; HSHIN1
• Summary. Alternatively spliced transcript variants have been found for this gene. The smaller protein isoform encoded by the shorter transcript variant is found only in HIV-1 infected cells. [provided by RefSeq, Jul 2010]
• Expression. Ubiquitous expression in testis (RPKM 19.7), bone marrow (RPKM 11.0) and 25 other tissues See more
• Preferred Names OTU domain-containing protein 4
• Names: HIV-1 induced protein HIN-1

Related articles in PubMed

1. HIV-1 promotor insertion revealed by selective detection of chimeric provirus-host gene transcripts. Raineri I, et al. Nucleic Acids Res, 1992 Dec 11. PMID 1475186, Free PMC Article https://www.ncbi.nlm.nih.gov/pubmed/1475186/
   This shows for the first time that HIV-1 can activate transcription of host cellular genes by promotor insertion in a fashion similar to slow-transforming avian and murine retroviruses.
2. OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling. Zhao Y, et al. Mol Cell, 2018 Feb 1. PMID 29395066 Ubiquitination is a major mechanism that regulates numerous cellular processes, including autophagy, DNA damage signaling, and inflammation. While hundreds of ubiquitin ligases exist to conjugate ubiquitin onto substrates, approximately 100 deubiquitinases (DUBs) are encoded by the human genome. Thus, deubiquitinases are likely regulated by unidentified mechanisms to target distinct substrates and cellular functions. Here, we demonstrate that the deubiquitinase OTUD4, which nominally encodes a K48-specific deubiquitinase, is phosphorylated near its catalytic domain, activating a latent K63-specific deubiquitinase. Besides phosphorylation, this latter activity requires an adjacent ubiquitin-interacting motif, which increases the affinity of OTUD4 for K63-linked chains. We reveal the Toll-like receptor (TLR)-associated factor MyD88 as a target of this K63 deubiquitinase activity. Consequently, TLR-mediated activation of NF-κB is negatively regulated by OTUD4, and macrophages from Otud4^-/- mice exhibit increased inflammatory signaling upon TLR stimulation. Our results reveal insights into how a deubiquitinase may modulate diverse processes through post-translational modification.
3. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. Margolin DH, et al. N Engl J Med, 2013 May 23. PMID 23656588, Free PMC Article
   
   
   (Suom. Seuraa vaikea harvinainen oireyhtymä, jos taustalla on sellainen kombinoitu mutaatio, jossa RBR-tyyppinen RNF proteiini RNF216, E3 ubikitiiniligaasi,  ja OTUD4,deubikitinaasi, ovat molemmat mutatoituneita geenejä )

See all (35) citations in PubMed
 
See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFWhat's a GeneRIF?s: Gene References Into Functions

1. There is an evolutionary loss of activity in de-ubiquitylating enzymes of the OTU family, OTUD4, otu, and CG3251.
2. OTUD4 is a positive regulator of ALKBH2 and ALKBH3, two DNA demethylases critical for alkylation repair. Repair of DNA alkylation damage is critical for genomic stability and involves multiple conserved enzymatic pathways. Alkylation damage resistance, which is critical in cancer chemotherapy, depends on the overexpression of alkylation repair proteins. However, the mechanisms responsible for this upregulation are unknown. Here, we show that an OTU domain deubiquitinase, OTUD4, is a positive regulator of ALKBH2 and ALKBH3, two DNA demethylases critical for alkylation repair. Remarkably, we find that OTUD4 catalytic activity is completely dispensable for this function. Rather, OTUD4 is a scaffold for USP7 and USP9X, two deubiquitinases that act directly on the AlkB proteins. Moreover, we show that loss of OTUD4, USP7, or USP9X in tumor cells makes them significantly more sensitive to alkylating agents. Taken together, this work reveals a novel, noncanonical mechanism by which an OTU family deubiquitinase regulates its substrates, and provides multiple new targets for alkylation chemotherapy sensitization of tumors.
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4475402/
   

Peptide history and structure:

 OTU domain-containing protein 4 isoform 3 [Homo sapiens]

NCBI Reference Sequence: NP_001096123.1
Identical Proteins FASTA Graphics

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LOCUS       NP_001096123            1049 aa            linear   PRI 24-JUN-2018
DEFINITION  OTU domain-containing protein 4 isoform 3 [Homo sapiens].
ACCESSION   NP_001096123
VERSION     NP_001096123.1
DBSOURCE    REFSEQ: accession NM_001102653.1
KEYWORDS    RefSeq.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (residues 1 to 1049)
  AUTHORS   Zhao Y, Mudge MC, Soll JM, Rodrigues RB, Byrum AK, Schwarzkopf EA,
            Bradstreet TR, Gygi SP, Edelson BT and Mosammaparast N.
  TITLE     OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates
            MyD88-Dependent Signaling
  JOURNAL   Mol. Cell 69 (3), 505-516 (2018)
   PUBMED   29395066
REFERENCE   2  (residues 1 to 1049)
  AUTHORS   Louis M, Hofmann K and Broemer M.
  TITLE     Evolutionary Loss of Activity in De-Ubiquitylating Enzymes of the
            OTU Family
  JOURNAL   PLoS ONE 10 (11), e0143227 (2015)
   PUBMED   26588485
  REMARK    GeneRIF: There is an evolutionary loss of activity in
            de-ubiquitylating enzymes of the OTU family, OTUD4, otu, and
            CG3251.
            Publication Status: Online-Only
REFERENCE   3  (residues 1 to 1049)
  AUTHORS   Zhao Y, Majid MC, Soll JM, Brickner JR, Dango S and Mosammaparast
            N.
  TITLE     Noncanonical regulation of alkylation damage resistance by the
            OTUD4 deubiquitinase
  JOURNAL   EMBO J. 34 (12), 1687-1703 (2015)
   PUBMED   25944111
  REMARK    GeneRIF: OTUD4 is a positive regulator of ALKBH2 and ALKBH3, two
            DNA demethylases critical for alkylation repair.
REFERENCE   4  (residues 1 to 1049)
  AUTHORS   Mevissen TE, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M,
            Arnaudo N, Ekkebus R, Kulathu Y, Wauer T, El Oualid F, Freund SM,
            Ovaa H and Komander D.
  TITLE     OTU deubiquitinases reveal mechanisms of linkage specificity and
            enable ubiquitin chain restriction analysis
  JOURNAL   Cell 154 (1), 169-184 (2013)
   PUBMED   23827681
REFERENCE   5  (residues 1 to 1049)
  AUTHORS   Margolin DH, Kousi M, Chan YM, Lim ET, Schmahmann JD,
            Hadjivassiliou M, Hall JE, Adam I, Dwyer A, Plummer L, Aldrin SV,
            O'Rourke J, Kirby A, Lage K, Milunsky A, Milunsky JM, Chan J,
            Hedley-Whyte ET, Daly MJ, Katsanis N and Seminara SB.
  TITLE     Ataxia, dementia, and hypogonadotropism caused by disordered
            ubiquitination
  JOURNAL   N. Engl. J. Med. 368 (21), 1992-2003 (2013)
   PUBMED   23656588
  REMARK    GeneRIF: The syndrome of hypogonadotropic hypogonadism, ataxia, and
            dementia can be caused by inactivating mutations in RNF216 or by
            the combination of mutations in RNF216 and OTUD4
REFERENCE   6  (residues 1 to 1049)
  AUTHORS   Beausoleil SA, Villen J, Gerber SA, Rush J and Gygi SP.
  TITLE     A probability-based approach for high-throughput protein
            phosphorylation analysis and site localization
  JOURNAL   Nat. Biotechnol. 24 (10), 1285-1292 (2006)
   PUBMED   16964243
REFERENCE   7  (residues 1 to 1049)
  AUTHORS   Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM,
            Polakiewicz RD and Comb MJ.
  TITLE     Immunoaffinity profiling of tyrosine phosphorylation in cancer
            cells
  JOURNAL   Nat. Biotechnol. 23 (1), 94-101 (2005)
   PUBMED   15592455
REFERENCE   8  (residues 1 to 1049)
  AUTHORS   Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villen J, Li
            J, Cohn MA, Cantley LC and Gygi SP.
  TITLE     Large-scale characterization of HeLa cell nuclear phosphoproteins
  JOURNAL   Proc. Natl. Acad. Sci. U.S.A. 101 (33), 12130-12135 (2004)
   PUBMED   15302935
REFERENCE   9  (residues 1 to 1049)
  AUTHORS   Brill LM, Salomon AR, Ficarro SB, Mukherji M, Stettler-Gill M and
            Peters EC.
  TITLE     Robust phosphoproteomic profiling of tyrosine phosphorylation sites
            from human T cells using immobilized metal affinity chromatography
            and tandem mass spectrometry
  JOURNAL   Anal. Chem. 76 (10), 2763-2772 (2004)
   PUBMED   15144186
REFERENCE   10 (residues 1 to 1049)
  AUTHORS   Raineri I and Senn HP.
  TITLE     HIV-1 promotor insertion revealed by selective detection of
            chimeric provirus-host gene transcripts
  JOURNAL   Nucleic Acids Res. 20 (23), 6261-6266 (1992)
   PUBMED   1475186
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from DB446926.2, BC118572.1 and
            AC096757.3.
            This sequence is a reference standard in the RefSeqGene project.
            
            Summary: Alternatively spliced transcript variants have been found
            for this gene. The smaller protein isoform encoded by the shorter
            transcript variant is found only in HIV-1 infected cells. [provided
            by RefSeq, Jul 2010].
            
            Transcript Variant: This variant (3) represents the longer
            transcript and encodes the longer isoform (3).
            
            Sequence Note: This RefSeq record was created from transcript and
            genomic sequence data because no single transcript was available
            for the full length of the gene. The extent of this transcript is
            supported by transcript alignments.
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: AK302581.1 [ECO:0000332]
            RNAseq introns              :: mixed/partial sample support
                                           SAMEA1965299, SAMEA1966682
                                           [ECO:0000350]
            ##Evidence-Data-END##
FEATURES             Location/Qualifiers
     source          1..1049
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="4"
                     /map="4q31.21"
     Protein         1..1049
                     /product="OTU domain-containing protein 4 isoform 3"
                     /EC_number="3.4.19.12"
                     /note="OTU domain-containing protein 4; HIV-1 induced
                     protein HIN-1"
                     /calculated_mol_wt=116951
     Region          <3 ..="">56
                     /region_name="OTU"
                     /note="OTU-like cysteine protease; cl19932"
                     /db_xref="CDD:303090"
     CDS             1..1049
                     /gene="OTUD4"
                     /gene_synonym="DUBA6; HIN1; HSHIN1"
                     /coded_by="NM_001102653.1:139..3288"
                     /note="isoform 3 is encoded by transcript variant 3"
                     /db_xref="CCDS:CCDS47139.1"
                     /db_xref="GeneID:54726"
                     /db_xref="HGNC:HGNC:24949"
                     /db_xref="MIM:611744"
ORIGIN      
        1 macihylren rekfeafieg sfeeylkrle npqewvgqve isalslmyrk dfiiyrepnv
       61 spsqvtennf pekvllcfsn gnhydivypi kykessamcq sllyellyek vfktdvskiv
      121 meldtlevad ednseisdse ddscksktaa aaadvngfkp lsgneqlknn gnstslplsr
      181 kvlkslnpav yrnveyeiwl kskqaqqkrd ysiaaglqye vgdkcqvrld hngkflnadv
      241 qgihsengpv lveelgkkht sknlkapppe swntvsgkkm kkpstsgqnf hsdvdyrgpk
      301 npskpikaps alpprlqhps gvrqhafssh ssgsqsqkfs sehknlsrtp sqiirkpdre
      361 rvedfdhtsr esnyfglspe errekqaiee srllyeiqnr deqafpalss ssvnqsasqs
      421 snpcvqrkss hvgdrkgsrr rmdteerkdk dsihghsqld krpepstlen itddkyatvs
      481 spskskklec pspaeqkpae hvslsnpapl lvspevhltp avpslpatvp awpsepttfg
      541 ptgvpapipv lsvtqtlttg pdsavsqahl tpspvpvsiq avnqplmplp qtlslyqdpl
      601 ypgfpcnekg draivppysl cqtgedlpkd knilrfffnl gvkayscpmw aphsylyplh
      661 qaylaacrmy pkvpvpvyph npwfqeapaa qnesdctctd ahfpmqteas vngqmpqpei
      721 gpptfssplv ippsqvsesh gqlsyqadle setpgqllha dyeeslsgkn mfpqpsfgpn
      781 pflgpvpiap pffphvwygy pfqgfienpv mrqnivlpsd ekgeldlsle nldlskdcgs
      841 vstvdefpea rgehvhslpe asvsskpdeg rteqssqtrk adtalasipp vaegkahppt
      901 qilnreretv pvelepkrti qslkektekv kdpktaadvv spgansvdsr vqrpkeesse
      961 denevsnilr sgrskqfynq tygsrkyksd wgysgrggyq hvrseeswkg qpsrsrdegy
     1021 qyhrnvrgrp frgdrrrsgm gdghrgqht
//

UCH-L5 (1q31.2) Ubikitiinin C-terminaalinen hydrolaasi (DUB perhettä)

UCH-L5 ( 1q31.2) ,

Ubiquitin C-terminal hydrolase L5

https://www.ncbi.nlm.nih.gov/gene/51377

Also known as  UCH37; CGI-70; INO80R; UCH-L5

Expression Ubiquitous expression in brain (RPKM 5.2), esophagus (RPKM 3.6) and 25 other tissues See more

Preferred Names

ubiquitin carboxyl-terminal hydrolase isozyme L5

Names

INO80 complex subunit R

ubiquitin C-terminal hydrolase UCH37

ubiquitin carboxyl-terminal esterase L5

ubiquitin carboxyl-terminal hydrolase L5

ubiquitin thioesterase L5

Related articles in PubMed

1. Positive cytoplasmic UCHL5 tumor expression in gastric cancer is linked to improved prognosis. Arpalahti L, et al. PLoS One, 2018. PMID 29474458, Free PMC Article
2. UCHL5 expression associates with improved survival in lymph-node-positive rectal cancer. Arpalahti L, et al. Tumour Biol, 2017 Jul. PMID 28681694
3. Nuclear ubiquitin C-terminal hydrolase L5 expression associates with increased patient survival in pancreatic ductal adenocarcinoma. Arpalahti L, et al. Tumour Biol, 2017 Jun. PMID 28653876
4. High expression of UCH37 is significantly associated with poor prognosis in human epithelial ovarian cancer. Wang L, et al. Tumour Biol, 2014 Nov. PMID 25123264
5. Expression and clinical significance of UCH37 in human esophageal squamous cell carcinoma. Chen Y, et al. Dig Dis Sci, 2012 Sep. PMID 22615012
   

See all (83) citations in PubMed
See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into Functions

1. Our studies provide a molecular mechanism by which UCHL5 mitigates TGFbeta-1 signaling by stabilizing Smad2/Smad3. These data indicate that UCHL5 may contribute to the pathogenesis of idiopathic pulmonary fibrosis and may be a potential therapeutic target.
2. Positive cytoplasmic UCHL5 tumor immunoexpression is linked to increased survival of patients with small (<5 66="" a="" age="" and="" cancer="" cm="" disease="" gastric="" i-ii="" in="" is="" marker="" new="" older="" or="" p="0.037)." potential="" prognostic="" relevance.="" stages="" thus="" tumors="" uchl5="" with="" years="">
3. our report demonstrates significant value in targeting USP14/UCHL5 with VLX1570 in drug-resistant Waldenstrom macroglobulinemia (WM) and carries a high potential for clinical translation
4. UCHL5 is a promising novel prognostic marker in lymph-node-positive rectal cancer. Our results also advance the currently limited knowledge of biomarkers in colorectal cancer treatment.
5. UCHL5 expression could function as a prognostic marker in pancreatic ductal adenocarcinoma, particularly at disease stages IIB to III. As UCHL5 is one of the few markers predicting increased survival, our results may be of clinical relevance.
6. this work implicates hRpn13 and Uch37 in cell cycle progression, providing a rationale for their function in cellular proliferation and for the apoptotic effect of the hRpn13-targeting molecule RA190.
7. These results uncover a novel mechanism for E2F1 transcriptional activation through removal of its Lys-63-linked ubiquitination by UCH37.
8. Uch37 consists of two domains, a globular UCH-domain and a fibrous C-terminal tail. The C-terminal residues of Uch37 are implicated in Rpn13 binding.
9. Data indicate that ubiquitin thioesterase L5 UCH37 (UCHL5) comprises a catalytic UCH domain followed by the four-helix (alpha8-alpha11) C-terminal domain.
10. Data show that DEUBAD domain in RPN13 (ADRM1) activates ubiquitin thioesterase L5 (UCH-L5), and the related DEUBAD domain in INO80G (NFRKB) inhibits UCH-L5.
    

Peptide history, structure: Articles from Finland in the latest news (2018) . Also news about  pulmonary fibrosis (2018) . https://www.ncbi.nlm.nih.gov/protein/NP_001186190.1

Conserved Domains (1) summary

cd02255
Location:8 → 223

Peptidase_C12; Cysteine peptidase C12 contains ubiquitin carboxyl-terminal hydrolase (UCH) families L1, L3, L5 and BAP1

Peptide structure: History and some News:

REFERENCE   1  (residues 1 to 328)
  AUTHORS   Arpalahti L, Laitinen A, Hagstrom J, Mustonen H, Kokkola A,
            Bockelman C, Haglund C and Holmberg CI.
  TITLE     Positive cytoplasmic UCHL5 tumor expression in gastric cancer is
            linked to improved prognosis
  JOURNAL   PLoS ONE 13 (2), e0193125 (2018)
 AUTHORS   Arpalahti L, Hagstrom J, Mustonen H, Lundin M, Haglund C and
            Holmberg CI.
  TITLE     UCHL5 expression associates with improved survival in
            lymph-node-positive rectal cancer
  JOURNAL   Tumour Biol. 39 (7), 1010428317716078 (2017)
   PUBMED   28681694
  REMARK    GeneRIF: UCHL5 is a promising novel prognostic marker in
            lymph-node-positive rectal cancer. Our results also advance the
            currently limited knowledge of biomarkers in colorectal cancer
            treatment.
REFERENCE   3  (residues 1 to 328)
AUTHORS   Arpalahti L, Saukkonen K, Hagstrom J, Mustonen H, Seppanen H,
            Haglund C and Holmberg CI.
  TITLE     Nuclear ubiquitin C-terminal hydrolase L5 expression associates
            with increased patient survival in pancreatic ductal adenocarcinoma
  JOURNAL   Tumour Biol. 39 (6), 1010428317710411 (2017)

AUTHORS   Nan L, Jacko AM, Tan J, Wang D, Zhao J, Kass DJ, Ma H and Zhao Y.
  TITLE     Ubiquitin carboxyl-terminal hydrolase-L5 promotes TGFbeta-1
            signaling by de-ubiquitinating and stabilizing Smad2/Smad3 in
            pulmonary fibrosis
  JOURNAL   Sci Rep 6, 33116 (2016)
   PUBMED   27604640
  REMARK    GeneRIF: Our studies provide a molecular mechanism by which UCHL5
            mitigates TGFbeta-1 signaling by stabilizing Smad2/Smad3. These
            data indicate that UCHL5 may contribute to the pathogenesis of
            idiopathic pulmonary fibrosis and may be a potential therapeutic
            target.
ORIGIN      
        1 mtgnagewcl mesdpgvfte likgfgcrga qveeiwslep enfeklkpvh gliflfkwqp
       61 geepagsvvq dsrldtiffa kqvinnacat qaivsvllnc thqdvhlget lsefkefsqs
      121 fdaamkglal snsdvirqvh nsfarqqmfe fdtktsakee dafhfvsyvp vngrlyeldg
      181 lregpidlga cnqddwisav rpviekriqk ysegeirfnl maivsdrkmi yeqkiaelqr
      241 qlaeepmdtd qgnsmlsaiq sevaknqmli eeevqklkry kienirrkhn ylpfimellk
      301 tlaehqqlip lvekakekqn akkaqetk
//

http://www.biochemsoctrans.org/content/ppbiost/34/5/761/F1.large.jpg