SIRT7 (17q25.3)
luokka III histonideasetylaasi
- Preferred Names
- NAD-dependent protein deacetylase sirtuin-7
- Names
- NAD-dependent deacetylase sirtuin-7
- SIR2-like protein 7
- regulatory protein SIR2 homolog 7
- silent mating type information regulation 2, S.cerevisiae, homolog 7
- sir2-related protein type 7
- sirtuin type 7
USP7 (deubikitinaasi) poistaa K63-ubikitiinin SIRT7 histonideasetylaasista ja täten säätelee glykolyysiä.
SIRT7 on luokan IV histoniasetylaasi ja osallistuu moniin
soluprosesseihin ja stressivaikutusten vastustamiseen esim. hypoxian,
matalan verensokerin ja DNA-vaurion vastustamiseen, SIRT7 on
linkkiytynyt glykolyysin kontrolliin, mikä osoittaa sille osaa
glukoosimetaboliassa. Myös jotkin transkriptionaaliset ja
posttranskriptionaaliset säätelymekanismit ovat mukana. Kuitenkin
on hyvin vähän tietoa siitä, miten SIRT7 säätyy
posttranslationaalisesti.
Tutkijat
identifioivat ubikitiinispesifisen peptidaasin USP7 (deubikitinaasin), joka on
SIRT7:n negatiivinen säätelijä. He osoittivat , että USP7
teki interaktion SIRT7:n kanssa sekä in vitro että in vivo
ja he osoittivat
myös, että SIRT7 käy läpi endogeenisen K63-polyubikitinaation,
jonka USP7 poistaa. Vaikka USP7-välitteisellä deubikitinaatiolla
ei ollut vaikutusta SIRT7:n stabiliteettiin, niin kuitenkin
deubikitinaatio vaimensi entsymaattista aktiivisuutta.
Tutkijat osoittivat
myös, että USP7 (deubikitinaasi) koordinoituu SIRT7:n kanssa
säätelemään glukoosi-6-fosfataasin katalyyttistä alayksikköä
(G6PC), joka on glukogeeninen geeni. USP7:n poisto
RNA-interferenssillä lisäsi sekä G6PC:n ilmentymää että
SIRT7:n entsymaattista aktiivisuutta. Lisäksi SIRT7 kohdentui
G6PC-promoottoriin transkriptiofaktorin ELJK4 kautta, mutta ei
FoxO1:n kautta. Yhteenvetona tutkimus antanee perustetta uusille
kliinisille lähestymistavoille glukoosiaineenvaihduntaa koskevien
metabolisten häiriöiden hoitoon.
LÄHDE:
J
Biol Chem. 2017 Aug 11;292(32):13296-13311. doi:
10.1074/jbc.M117.780130. Epub 2017 Jun 27. Ubiquitin-specific
peptidase 7 (USP7)-mediated deubiquitination of the histone
deacetylase SIRT7 regulates gluconeogenesis.Jiang
L1, Xiong
J1, Zhan
J1, Yuan
F1, Tang
M1, Zhang
C1, Cao
Z1, Chen
Y1, Lu
X1, Li
Y1, Wang
H1, Wang
L1, Wang
J2, Zhu
WG3,4,5, Wang
H6.Abstract
-
Sirtuin 7 (SIRT7), a member of the NAD+-dependent class III histone deacetylases, is involved in the regulation of various cellular processes and in resisting various stresses, such as hypoxia, low glucose levels, and DNA damage. Interestingly, SIRT7 is linked to the control of glycolysis, suggesting a role in glucose metabolism. Given the important roles of SIRT7, it is critical to clarify how SIRT7 activity is potentially regulated. It has been reported that some transcriptional and post-transcriptional regulatory mechanisms are involved. However, little is known how SIRT7 is regulated by the post-translational modifications.
-
Here, we identified ubiquitin-specific peptidase 7 (USP7), a deubiquitinase, as a negative regulator of SIRT7. We showed that USP7 interacts with SIRT7 both in vitro and in vivo, and we further demonstrated that SIRT7 undergoes endogenous Lys-63-linked polyubiquitination, which is removed by USP7. Although the USP7-mediated deubiquitination of SIRT7 had no effect on its stability, the deubiquitination repressed its enzymatic activity.
- We also showed that USP7 coordinates with SIRT7 to regulate the expression of glucose-6-phosphatase catalytic subunit (G6PC), a gluconeogenic gene. USP7 depletion by RNA interference increased both G6PC expression and SIRT7 enzymatic activity. Moreover, SIRT7 targeted the G6PC promoter through the transcription factor ELK4 but not through forkhead box O1 (FoxO1). In summary, SIRT7 is a USP7 substrate and has a novel role as a regulator of gluconeogenesis.
- Our study may provide the basis for new clinical approaches to treat metabolic disorders related to glucose metabolism. KEYWORDS: deubiquitylation (deubiquitination); gene expression; gluconeogenesis; post-translational modification; sirtuin PMID: 28655758 PMCID: PMC5555190[Available on 2018-08-11] DOI: 10.1074/jbc.M117.780130 [Indexed for MEDLINE]
SIRT7 on
histonidesuksinylaasi, joka linkitsee funktionaalisesti kromatiinin
tiivistymisen genomin stabiiliuteen.
Article | Open | Published:
20 July 2016
-
SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability Lei Li, Lan Shi et al. Nature Communications volume 7, Article number: 12235 (2016) | Download Citation
Vaikka SIRT7
sirtuiiniperheen jäsenenä kuvataan NAD+:sta -riippuvaisena luokan
III histonideasetylaasina, sen sisäinen entsyymiaktiivisuus on
ollut vielä tutkimatta, samoin sen soluominaisuudet (ennen vuotta
2016). Tässä työssä tutkijat raportoivat, että SIRT7 on NAD+:sta
riippuva histonidesuksinylaasi.He osoittivat, että SIR7 rekrytoituu
DNA:n kahden nauhan katkokseen (kaksoiskatkokseen) PARP1:stä riippuvalla tavalla ja
katalysoi siinä histonin H3K122 de-suksinylaation edistäen
kromatiinin tiivistymisen ja DSB:n korjaantumisen.
Tutkijat osoittivat,
että SIRT7:n poistaminen huonontaa kromatiinin tiivistymistä
DNA-vauriovasteessa ja herkistää soluja genotoksisille stresseille.
Tutkimus osoittaa SIRT7:n olevan histonidesuksinylaasi, mistä saa
käsitystä tämän sirtuiiniproteiinin epigeneettisen säätelyn
perustasta. Tutkijoiden kokeet paljastivat, että SIRT7:n katalysoima
H3K122-desuksinylaatio on kriittinen tapahtuma DNA-vauriovasteena ja
solun elossapysymisessä, mikä valottaa mekanistisesti SIRT7:n
solufunktiota.
-
Although SIRT7 is a member of sirtuin family proteins that are described as NAD+-dependent class III histone deacetylases, the intrinsic enzymatic activity of this sirtuin protein remains to be investigated and the cellular function of SIRT7 remains to be explored. Here we report that SIRT7 is an NAD+-dependent histone desuccinylase. We show that SIRT7 is recruited to DNA double-strand breaks (DSBs) in a PARP1-dependent manner and catalyses desuccinylation of H3K122 therein, thereby promoting chromatin condensation and DSB repair.
- We demonstrate that depletion of SIRT7 impairs chromatin compaction during DNA-damage response and sensitizes cells to genotoxic stresses. Our study indicates SIRT7 is a histone desuccinylase, providing a molecular basis for the understanding of epigenetic regulation by this sirtuin protein. Our experiments reveal that SIRT7-catalysed H3K122 desuccinylation is critically implemented in DNA-damage response and cell survival, providing a mechanistic insight into the cellular function of SIRT7.
https://www.researchgate.net/publication/313851028_SIRT7-dependent_deacetylation_of_CDK9_activates_RNA_polymerase_II_transcription
Abstract
SIRT7 is an NAD +-dependent protein deacetylase that regulates cell growth and proliferation. Previous studies have shown that SIRT7 is required for RNA polymerase I (Pol I) transcription and pre-rRNA processing. Here, we took a proteomic approach to identify novel molecular targets and characterize the role of SIRT7 in non-nucleolar processes. We show that SIRT7 interacts with numerous proteins involved in transcriptional regulation and RNA metabolism, the majority of interactions requiring ongoing transcription. In addition to its role in Pol I transcription, we found that SIRT7 also regulates transcription of snoRNAs and mRNAs. Mechanistically, SIRT7 promotes the release of P-TEFb from the inactive 7SK snRNP complex and deacetylates CDK9, a subunit of the elongation factor P-TEFb, which activates transcription by phosphorylating serine 2 within the C-terminal domain (CTD) of Pol II. SIRT7 counteracts GCN5-directed acetylation of lysine 48 within the catalytic domain of CDK9, deacetylation promoting CTD phosphorylation and transcription elongation.
(PDF) SIRT7-dependent deacetylation of CDK9 activates RNA polymerase II transcription. Available from: https://www.researchgate.net/publication/313851028_SIRT7-dependent_deacetylation_of_CDK9_activates_RNA_polymerase_II_transcription [accessed Jul 12 2018].
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