TY - JOUR
T1 - SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks
AU - Kapoor-Vazirani, Priya
AU - Rath, Sandip K.
AU - Liu, Xu
AU - Shu, Zhen
AU - Bowen, Nicole E.
AU - Chen, Yitong
AU - Haji-Seyed-Javadi, Ramona
AU - Daddacha, Waaqo
AU - Minten, Elizabeth V.
AU - Danelia, Diana
AU - Farchi, Daniela
AU - Duong, Duc M.
AU - Seyfried, Nicholas T.
AU - Deng, Xingming
AU - Ortlund, Eric A.
AU - Kim, Baek
AU - Yu, David S.
N1 - Funding Information:
We thank Dr. Roger Greenberg for U20S-235 mCherry-LacI-Fok1 cells, Dr. Jeremy Stark for U20S-DR-GFP cells, Dr. Gaelle Legube for AsiSI-ER-U2OS cells, and Dr. David Gius for PECE-SIRT1-FLAG WT and H363Y plasmids. We thank members of the Yu lab for their helpful discussion and technical expertize. We thank Dr. Pritha Bagchi (Emory Integrated Proteomics Core) for helpful discussion with mass spectrometry data. This work was supported by: 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.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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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U2 - 10.1038/s41467-022-34578-x
DO - 10.1038/s41467-022-34578-x
M3 - Article
C2 - 36344525
AN - SCOPUS:85141487211
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 6707
ER -