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 and David S. Yu ()
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Priya Kapoor-Vazirani: Emory University School of Medicine
Sandip K. Rath: Emory University School of Medicine
Xu Liu: Emory University School of Medicine
Zhen Shu: Emory University School of Medicine
Nicole E. Bowen: Emory University School of Medicine
Yitong Chen: Emory University School of Medicine
Ramona Haji-Seyed-Javadi: Emory University School of Medicine
Waaqo Daddacha: Medical College of Georgia at Augusta University
Elizabeth V. Minten: Emory University School of Medicine
Diana Danelia: Emory University School of Medicine
Daniela Farchi: Emory University School of Medicine
Duc M. Duong: Emory University School of Medicine
Nicholas T. Seyfried: Emory University School of Medicine
Xingming Deng: Emory University School of Medicine
Eric A. Ortlund: Emory University School of Medicine
Baek Kim: Emory University School of Medicine
David S. Yu: Emory University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34578-x

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