Premium
SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair
Author(s) -
Vazquez Berta N,
Thackray Joshua K,
Simonet Nicolas G,
KaneGoldsmith Noriko,
MartinezRedondo Paloma,
Nguyen Trang,
Bunting Samuel,
Vaquero Alejandro,
Tischfield Jay A,
Serrano Lourdes
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201593499
Subject(s) - biology , non homologous end joining , homologous recombination , dna , genetics , dna repair , genome , homologous chromosome , microbiology and biotechnology , computational biology , gene
Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT 7 targets acetylated lysine in the N‐terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT 7 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, SIRT 7‐deficient cells display increased replication stress and impaired DNA repair. SIRT 7 is recruited in a PARP 1‐dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53 BP 1 to DNA double‐strand breaks ( DSB s), thereby influencing the efficiency of non‐homologous end joining ( NHEJ ). These results reveal a direct role for SIRT 7 in DSB repair and establish a functional link between SIRT 7‐mediated H3K18 deacetylation and the maintenance of genome integrity.