SIRT6 Recruits SNF2H to DNA Break Sites, Preventing Genomic Instability Through Chromatin Remodeling

Debra Toiber, Fabian Erdel, Karim Bouazoune, Dafne M. Silberman, Lei Zhong, Peter Mulligan, Carlos Sebastian, Claudia Cosentino, Barbara Martinez-Pastor, Sofia Giacosa, Agustina D'Urso, Anders M. Näär, Robert Kingston, Karsten Rippe, Raul Mostoslavsky

Research output: Contribution to journalArticlepeer-review


DNA damage is linked to multiple human diseases, such as cancer, neurodegeneration, and aging. Little is known about the role of chromatin accessibility in DNA repair. Here, we find that the deacetylase sirtuin 6 (SIRT6) is one of the earliest factors recruited todouble-strand breaks (DSBs). SIRT6 recruits the chromatin remodeler SNF2H to DSBs and focally deacetylates histone H3K56. Lack of SIRT6 and SNF2H impairs chromatin remodeling, increasing sensitivity to genotoxic damage and recruitment of downstream factors such as 53BP1 and breast cancer 1 (BRCA1). Remarkably, SIRT6-deficient mice exhibit lower levels of chromatin-associated SNF2H in specific tissues, a phenotype accompanied by DNA damage. We demonstrate that SIRT6 is critical for recruitment of a chromatin remodeler as an early step in the DNA damage response, indicating that proper unfolding of chromatin plays a rate-limiting role. We present a unique crosstalk between a histone modifier and a chromatin remodeler, regulating a coordinated response to prevent DNA damage.

Original languageAmerican English
Pages (from-to)454-468
Number of pages15
JournalMolecular Cell
Issue number4
StatePublished - 22 Aug 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology


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