SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks

• Type of Material: Article
• Authors: Priya Kapoor-Vazirani, Emory University; Sandip K. Rath, Emory University; Xu Liu, Emory University; Zhen Shu, Emory University; Nicole E. Bowen, Emory University; Yitong Chen, Emory University; Ramona Haji-Seyed-Javadi, Emory University; Waaqo Daddacha, Augusta University; Elizabeth Minten, Emory University; Diana Danelia, Emory University; Daniela Farchi, Emory University; Duc M. Duong, Emory University; Nicholas Seyfried, Emory University; Xingming Deng, Emory University; Eric Ortlund, Emory University; Baek Kim, Emory University; David Yu, Emory University
• Language: English
• Date: 2022-11-07
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-022-34578-x
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 13
• Issue: 1
• Start Page: 6707
• End Page: 6707
• Grant/Funding Information: National Institutes of Health (NIH) National Cancer Institute (NCI) (R01CA178999 and R01CA254403 to D.S.Y.); Department of Defense Breast Cancer Research Program (BC180883 to D.S.Y.); NIH (R01 CA255257 to X.D.); NIH (AI136581 and AI162633 to B.K.) and NIH (F31 AI157884 to N.E.B.). Research reported in this publication was supported in part by the Emory Integrated Genomics Core (EIGC) Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
• Keywords: DAMAGE RESPONSE; INFECTION; Science & Technology; HIV-1 RESTRICTION; AICARDI-GOUTIERES SYNDROME; PROTEIN; ENDONUCLEASE; REPAIR; RESTRICTION FACTOR SAMHD1; Science & Technology - Other Topics; Multidisciplinary Sciences; DEOXYNUCLEOTIDE TRIPHOSPHOHYDROLASE ACTIVITY; DNTP LEVELS
• Research Categories: Biology, Genetics

Abstract

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) has a dNTPase-independent function in promoting DNA end resection to facilitate DNA double-strand break (DSB) repair by homologous recombination (HR); however, it is not known if upstream signaling events govern this activity. Here, we show that SAMHD1 is deacetylated by the SIRT1 sirtuin deacetylase, facilitating its binding with ssDNA at DSBs, to promote DNA end resection and HR. SIRT1 complexes with and deacetylates SAMHD1 at conserved lysine 354 (K354) specifically in response to DSBs. K354 deacetylation by SIRT1 promotes DNA end resection and HR but not SAMHD1 tetramerization or dNTPase activity. Mechanistically, K354 deacetylation by SIRT1 promotes SAMHD1 recruitment to DSBs and binding to ssDNA at DSBs, which in turn facilitates CtIP ssDNA binding, leading to promotion of genome integrity. These findings define a mechanism governing the dNTPase-independent resection function of SAMHD1 by SIRT1 deacetylation in promoting HR and genome stability.