SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair

Berta N. Vazquez, Joshua K. Thackray, Nicolas G. Simonet, Noriko Kane-Goldsmith, Paloma Martinez-Redondo, Trang Nguyen, Samuel Bunting, Alejandro Vaquero, Jay A. Tischfield, Lourdes Serrano

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N-terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7-knockout mice suffer from partial embryonic lethality and a progeroid-like phenotype. Consistently, SIRT7-deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1-dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double-strand breaks (DSBs), thereby influencing the efficiency of non-homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7-mediated H3K18 deacetylation and the maintenance of genome integrity.

Original languageEnglish (US)
Pages (from-to)1488-1503
Number of pages16
JournalEMBO Journal
Volume35
Issue number14
DOIs
StatePublished - Jul 15 2016

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Keywords

  • DNA damage
  • PARP1
  • SIRT7
  • histone acetylation
  • non-homologous end joining

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