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

doi:10.1038/s41467-022-34578-x

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

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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 language	English (US)
Article number	6707
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34578-x
State	Published - Dec 2022

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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Kapoor-Vazirani, P., Rath, S. K., Liu, X., Shu, Z., Bowen, N. E., Chen, Y., Haji-Seyed-Javadi, R., Daddacha, W., Minten, E. V., Danelia, D., Farchi, D., Duong, D. M., Seyfried, N. T., Deng, X., Ortlund, E. A., Kim, B., & Yu, D. S. (2022). SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks. Nature communications, 13(1), Article 6707. https://doi.org/10.1038/s41467-022-34578-x

Kapoor-Vazirani, P, Rath, SK, Liu, X, Shu, Z, Bowen, NE, Chen, Y, Haji-Seyed-Javadi, R, Daddacha, W, Minten, EV, Danelia, D, Farchi, D, Duong, DM, Seyfried, NT, Deng, X, Ortlund, EA, Kim, B & Yu, DS 2022, 'SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks', Nature communications, vol. 13, no. 1, 6707. https://doi.org/10.1038/s41467-022-34578-x

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title = "SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks",

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.",

author = "Priya Kapoor-Vazirani and Rath, {Sandip K.} and Xu Liu and Zhen Shu and Bowen, {Nicole E.} and Yitong Chen and Ramona Haji-Seyed-Javadi and Waaqo Daddacha and Minten, {Elizabeth V.} and Diana Danelia and Daniela Farchi and Duong, {Duc M.} and Seyfried, {Nicholas T.} and Xingming Deng and Ortlund, {Eric A.} and Baek Kim and Yu, {David S.}",

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doi = "10.1038/s41467-022-34578-x",

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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.

PY - 2022/12

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

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