BRCA2 (13q13.1), DNA DSB-vauriota korjaavan kompleksin alayksikkö

Kommenttia:  BRCA ja BRC2 geenit sijaitsevat eri kromosomeissa ( 17 ja vastaavasti 13). Kuitenkin toiminnallisedsti ne vaikuttavat yhdessä  kompleksina ja vastaavat genomin stabiiliudesta ja  DNA:n kaksoisjuostevaurion korjaamisesta  HR- tietä.  Tässä on  PubMed tietoa   BRCA2- geenistä. Näitä molempia  tutkitaan  paljon ja niiden mutaatioilta on merkitystä kemoterapian valintaan. Hyvin uusia artikkeleita on joukossa mainittuna.

BRCA2, DNA repair associated (13q13.1)

https://www.ncbi.nlm.nih.gov/gene/675
 Synonyms  FAD; FACD; FAD1; GLM3; BRCC2; FANCD; PNCA2; FANCD1; XRCC11; BROVCA2

Summary. Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination (HR) pathway for double-strand DNA repair. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, Dec 2008]

Expression- Broad expression in bone marrow (RPKM 2.9), testis (RPKM 2.2) and 17 other tissues See more

Preferred Names

breast cancer type 2 susceptibility protein

Names

BRCA1/BRCA2-containing complex, subunit 2

Fanconi anemia group D1 protein

breast and ovarian cancer susceptibility gene, early onset

breast and ovarian cancer susceptibility protein 2

breast cancer 2 tumor suppressor

breast cancer 2, early onset

mutant BRCA2

truncated breast cancer 2

 Peptide3418 aminoacids.

Conserved Domains (5) summary

 

cd04494
Location:2804 → 3054

BRCA2DBD_OB2; BRCA2DBD_OB2: A subfamily of OB folds corresponding to the second OB fold (OB2) of the 800-amino acid C-terminal ssDNA binding domain (DBD) of BRCA2 (breast cancer susceptibility gene 2) protein, called BRCA2DBD. BRCA2 participates in homologous recombination-mediated repair of double-strand DNA breaks. It stimulates the displacement of Replication protein A (RPA), the most abundant eukaryotic ssDNA binding protein. It also facilitates filament formation. Mutations that map throughout the BRCA2 protein are associated with breast cancer susceptibility. BRCA2 is a large nuclear protein and its most conserved region is the C-terminal BRCA2DBD. BRCA2DBD binds ssDNA in vitro, and is composed of five structural domains, three of which are OB folds (OB1, OB2, and OB3). BRCA2DBD OB2 and OB3 are arranged in tandem, and their mode of binding can be considered qualitatively similar to two OB folds of RPA1, DBD-A and DBD-B (the major DBDs of RPA).

pfam00634
Location:1518 → 1549

BRCA2; BRCA2 repeat

pfam09103
Location:2670 → 2793

BRCA-2_OB1; BRCA2, oligonucleotide/oligosaccharide-binding, domain 1

pfam09104
Location:3057 → 3186

BRCA-2_OB3; BRCA2, oligonucleotide/oligosaccharide-binding, domain 3

pfam09169
Location:2481 → 2667

BRCA-2_helical; BRCA2, helical

(Kommentti: Tämä on erittäin tutkittu merkitsijägeeni ja -proteiini . Kts. Esim wikipdiatieto ja hyvä kuva https://en.wikipedia.org/wiki/BRCA2) Geenin tehtävä on tuottaa proteiinia, joka osallistuu DNA-vaurion korjaamiseen. Otan PubMed hakulaiteella BRCA2: sta 7 uusinta artikkelia vuodelta 2019 ensin):

Search results

Items: 1 to 20 of 10058 Page of 503

Select item 311016861.

Uptake of testing for germline BRCA mutations in patients with non-mucinous epithelial ovarian cancers in Western Australia: a comparison of different genetic counseling methods.

Stearnes G, Nichols CB, Schofield L, O'Sullivan S, Pachter N, Cohen PA.

Int J Gynecol Cancer. 2019 May 17. pii: ijgc-2019-000389. doi: 10.1136/ijgc-2019-000389. [Epub ahead of print]

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Select item 310996883. The Role of BRCA Testing in Hereditary Pancreatic and Prostate Cancer Families. Pilarski R. Am Soc Clin Oncol Educ Book. 2019 Jan;(39):79-86. doi: 10.1200/EDBK_238977. Similar articles

Select item 310996314. The Evolving Landscape of Chemotherapy in Newly Diagnosed Advanced Epithelial Ovarian Cancer. Monk BJ, Randall LM, Grisham RN. Am Soc Clin Oncol Educ Book. 2019 Jan;(39):e141-e151. doi: 10.1200/EDBK_239007.1 Similar articles

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Select item 310957756. Investigating the relationship between BRCA1 and BRCA2 genes methylation profile and sperm DNA fragmentation in infertile men. Kabartan E, Gunes S, Arslan MA, Asci R. Andrologia. 2019 May 16:e13308. doi: 10.1111/and.13308. [Epub ahead of print] Similar articles

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(Kommentti: BRCA2- Geeni-informaatioon liittyviä artikkeleita, jotka PubMed on seulonut esitettäväksi)

Related articles in PubMed

1. The Post-Synaptic Function of Brca2. Wang CX, et al. Sci Rep, 2019 Mar 14. PMID 30872704, Free PMC Article
2. Prevalence of germline BRCA mutations among women with carcinoma of the peritoneum or fallopian tube. Choi MC, et al. J Gynecol Oncol, 2018 Jul. PMID 29770616, Free PMC Article
3. Long non-coding RNA RP11-552M11.4 promotes cells proliferation, migration and invasion by targeting BRCA2 in ovarian cancer. Huang K, et al. Cancer Sci, 2018 May. PMID 29478268, Free PMC Article
4. No Evidence for the Pathogenicity of the BRCA2 c.6937 + 594T>G Deep Intronic Variant: A Case-Control Analysis. Dutil J, et al. Genet Test Mol Biomarkers, 2018 Feb. PMID 29356578, Free PMC Article
5. BRCA2 antagonizes classical and alternative nonhomologous end-joining (NHEJ) to prevent gross genomic instability. Han J, et al. Nat Commun, 2017 Nov 13. PMID 29133916, Free PMC Article
   

See all (1721) citations in PubMed
See citations in PubMed for homologs of this gene provided by HomoloGene

GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

1. These results suggest a modest association between BRCA1 and BRCA2 and Nonsyndromic cleft lip with or without cleft palate.
2. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database.
3. Study shows that BRCA1, PALB2 and BRCA2 can all play a significant role in both checkpoint activation and checkpoint maintenance, depending on cell type and context, and that PALB2 links BRCA1 and BRCA2 in the checkpoint response. The BRCA1-PALB2 interaction can be important for checkpoint activation, whereas PALB2-BRCA2 complex appears to be more critical for checkpoint maintenance.
4. Our results did not provide evidence for elevated risks of invasivebreast cancer (BC) or epithelial ovarian cancer in BRCA1/BRCA2 predictive test negatives
5. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
6. BRCA1/2 mutation prevalence in unselected breast cancer patients was 1.8%.
7. The prevalence of germline BRCA1/2 mutations in patients with peritoneal carcinoma or fallopian tube carcinoma is comparable to that of BRCA1/2 mutations in epithelial ovarian cancer patients.
8. Prevalence of BRCA1/2 germline pathogenic (P) and likely pathogenic (LP) variants is slightly higher than previously described by the largest occidental studies, with a high prevalence of variant c.5266dupC (p.Gln1756Profs*74) in BRCA1 observed. Moreover, we identified a new LP variant.
9. Population-Based BRCA1/2 Testing in Ashkenazi Jews: Ready for Prime Time.
10. RAD51 can dissociate the very D-loops they create if in stoichiometric excess. BRCA2 regulates HR at a post-synaptic stage by modulating RAD51-mediated D-loop dissociation. Provides a biochemical mechanistic underpinning of homeostasis between RAD51 and BRCA2 previously reported in cellular experiments.
    

Submit: New GeneRIF Correction See all GeneRIFs (1218)

Kommentti: Mikä osuus on USP21 deubikitinaasilla  BRCA2_proteiinin stabilisoitumsieen DSB DA vauriokohdalla?
ERÄS NÄKÖKOHTA BRCA2-proteiinin merkityksestä.

(Suomennosta artikkelista alla )  BRCA2  korjaa DNAvauriota.  Deubikitinaasi USB21 joka on hyvin monifunktioinen,  pystyy mys spesifisesti poistamaan  ubikitiinejä BRCA2 molekylistä joka on asettunut DSB DNA vaurion  ylle vaurionkorjauksen aikana.  Täten USB21 kunto vaikuttaa myös BRCA2-proteiinin   funktioon.   eräs näkökohta  :
 Suomennosta abstraktista:
 Tuumorikasvukin luottaa  solun tehokkaaseen kykyyn korjata  DNA-vaurioita, jolloin vähenisi tuumoria   itseään haittaavat   DNA-vauriot,  joita tulee solujen  liiallisesta jakautumisesta.
  Tämän takia malignin kasvun manipulaatioon  tarjoutuu  lupaavia strategioita  DNA-korjausfunktion  moduloimisesta.
 Tutkijat ovat tunnistaneet  ubikitiinispesifisen proteaasin USP21(joka on  DUB-molekyyli)   ja  BRCA2-  proteiinin  positiivinen  säätelijä.
BRCA2 taas on  avainasemassa oleva  välittäjämolekyyli DNA:n korjaamisessa  HR- tietä ( homologinen rekombinaatiotie).
USP21 -deubikitinaasi tekee interaktion BRAC2:n kanssa  ja poistaa siitä ubikitiinejä  ja stabilisoi täten BRCA2:n edistämään  tehokaksti  RAD51- tekijän latautumista  DNA:n katkeamakohtaan(DSB).
Sen takia USP21- deubikitinaasin  poistaminen solusta vähentää HR-korjaustien tehokkuutta ja  aiheuttaa lisää DNA-vauriokertymää ja  haittaa tuumorisolun elossapysymistä.
Tärkeä huomata, että  BRCA2:n  yli-ilmentyminen  palauttaa osittain  USP21:een liittyneen    elossapysymisvajeen.
Lisäksi tutkijat ovat osoittaneet, että USP21 yli-ilmenee maksasolusyövässä ja silloin se edistää BRCA2-proteiinin stabiilisuutta,  minkä vaikutus potilaan elossapysymiseen on käänteinen.
Yhtgeenvetona tutkiojoiden löydökset tunnistavat  deubikitinaation tavaksi, mikkä BRCA2 -funktio säätyy ja he viittaavat USP21- deubikitinaasin olevan mahdollinen terapeuttinen kohde   tuumoreissa joissa BRCA2 on taitavana vaikuttajana.   
Ja koska  BRCA2 on essentielli DNA-vaurion korjaamisessa, siinä ilmenevät puutteet taas  toisalta liittyvät tumorigeneesiin ja lisäksi lisääntyneeseen alttiuteen genotoksiselle stressille.
Tässä  tutkimustyössään  kirjoittajat osoittavat, että  USP21 (DUB)  säätelemällä BRCA2:n stabiiliutta  säätelee  tuumorisolujen kykyä korjata  DNA-vaurioita.

•  https://www.ncbi.nlm.nih.gov/pubmed/28743957
• Abstract. Tumor growth relies on efficient DNA repair to mitigate the detrimental impact of DNA damage associated with excessive cell division. Modulating repair factor function, thus, provides a promising strategy to manipulate malignant growth. Here, we identify the ubiquitin-specific protease USP21 as a positive regulator of BRCA2, a key mediator of DNA repair by homologous recombination. USP21 interacts with, deubiquitinates and stabilizes BRCA2 to promote efficient RAD51 loading at DNA double-strand breaks. As a result, depletion of USP21 decreases homologous recombination efficiency, causes an increase in DNA damage load and impairs tumor cell survival. Importantly, BRCA2 overexpression partially restores the USP21-associated survival defect. Moreover, we show that USP21 is overexpressed in hepatocellular carcinoma, where it promotes BRCA2 stability and inversely correlates with patient survival. 
•  Together, our findings identify deubiquitination as a means to regulate BRCA2 function and point to USP21 as a potential therapeutic target in BRCA2-proficient tumors.BRCA2 is essential for the repair of DNA damage; therefore, defects in BRCA2 are associated with tumorigenesis but also with increased susceptibility to genotoxic stress. Here the authors show that USP21 regulates the ability of tumor cells to repair damaged DNA by regulating BRCA2 stability.