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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number6707
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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