SAMHD1 Deacetylation by SIRT1 Promotes DNA End Resection by Facilitating DNA Binding at Double-strand Breaks

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Nov 7

PMID 36344525

Authors

Priya Kapoor-Vazirani

Sandip K Rath

Xu Liu

Zhen Shu

Nicole E Bowen

Yitong Chen

Ramona Haji-Seyed-Javadi

Waaqo Daddacha

Elizabeth V Minten

Diana Danelia

Daniela Farchi

Duc M Duong

Nicholas T Seyfried

Xingming Deng

Eric A Ortlund

Baek Kim

David S Yu

Affiliations

Soon will be listed here.

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.

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