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

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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)

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.

Suggested Citation

  • 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. D, 2022. "SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34578-x
    DOI: 10.1038/s41467-022-34578-x
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