SIRT1 regulates DNA damage signaling through the PP4 phosphatase complex Journal Article


Authors: Rasti, G.; Becker, M.; Vazquez, B. N.; Espinosa-Alcantud, M.; Fernandez-Duran, I.; Gamez-Garcia, A.; Ianni, A.; Gonzalez, J.; Bosch-Presegue, L.; Marazuela-Duque, A.; Guitart-Solanes, A.; Segura-Bayona, S.; Bech-Serra, J. J.; Scher, M.; Serrano, L.; Shankavaram, U.; Erdjument-Bromage, H.; Tempst, P.; Reinberg, D.; Olivella, M.; Stracker, T. H.; de la Torre, C.; Vaquero, A.
Article Title: SIRT1 regulates DNA damage signaling through the PP4 phosphatase complex
Abstract: The Sirtuin family of NAD(+)-dependent enzymes plays an important role in maintaining genome stability upon stress. Several mammalian Sirtuins have been linked directly or indirectly to the regulation of DNA damage during replication through Homologous recombination (HR). The role of one of them, SIRT1, is intriguing as it seems to have a general regulatory role in the DNA damage response (DDR) that has not yet been addressed. SIRT1-deficient cells show impaired DDR reflected in a decrease in repair capacity, increased genome instability and decreased levels of gamma H2AX. Here we unveil a close functional antagonism between SIRT1 and the PP4 phosphatase multiprotein complex in the regulation of the DDR. Upon DNA damage, SIRT1 interacts specifically with the catalytical subunit PP4c and promotes its inhibition by deacetylating the WH1 domain of the regulatory subunits PP4R3 alpha/beta. This in turn regulates gamma H2AX and RPA2 phosphorylation, two key events in the signaling of DNA damage and repair by HR. We propose a mechanism whereby during stress, SIRT1 signaling ensures a global control of DNA damage signaling through PP4.
Keywords: homologous recombination; breast; protein; tumorigenesis; repair; atm; deacetylase; histone h2ax phosphorylation; sirtuins; rpa2
Journal Title: Nucleic Acids Research
Volume: 51
Issue: 13
ISSN: 0305-1048
Publisher: Oxford University Press  
Date Published: 2023-07-21
Start Page: 6754
End Page: 6769
Language: English
ACCESSION: WOS:001006433600001
DOI: 10.1093/nar/gkad504
PROVIDER: wos
PMCID: PMC10359614
PUBMED: 37309898
Notes: Article -- Source: Wos
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Paul J Tempst
    324 Tempst