RT Journal Article
SR Electronic
T1 SIRT1 regulates DNA damage signaling through the PP4 phosphatase complex
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.09.29.510108
DO 10.1101/2022.09.29.510108
A1 George Rasti
A1 Maximilian Becker
A1 Berta N. Vazquez
A1 Maria Espinosa-Alcantud
A1 Irene Fernández-Duran
A1 Andrés Gámez-García
A1 Jessica Gonzalez-Nieto
A1 Laia Bosch-Presegué
A1 Anna Marazuela-Duque
A1 Sandra Segura-Bayona
A1 Alessandro Ianni
A1 Joan-Josep Bech-Serra
A1 Michael Scher
A1 Lourdes Serrano
A1 Uma Shankavaram
A1 Hediye Erdjument-Bromage
A1 Paul Tempst
A1 Danny Reinberg
A1 Mireia Olivella
A1 Travis Stracker
A1 Carolina de la Torre
A1 Alejandro Vaquero
YR 2022
UL http://biorxiv.org/content/early/2022/09/30/2022.09.29.510108.abstract
AB 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 γH2AX. 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 PP4R3α/β. This in turn regulates γH2AX 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.Competing Interest StatementThe authors have declared no competing interest.