TY - JOUR
T1 - SIRT6 Recruits SNF2H to DNA Break Sites, Preventing Genomic Instability Through Chromatin Remodeling
AU - Toiber, Debra
AU - Erdel, Fabian
AU - Bouazoune, Karim
AU - Silberman, Dafne M.
AU - Zhong, Lei
AU - Mulligan, Peter
AU - Sebastian, Carlos
AU - Cosentino, Claudia
AU - Martinez-Pastor, Barbara
AU - Giacosa, Sofia
AU - D'Urso, Agustina
AU - Näär, Anders M.
AU - Kingston, Robert
AU - Rippe, Karsten
AU - Mostoslavsky, Raul
N1 - Funding Information:
This work was supported in part by NIH grant GM093072-01 (R.M.). R.M is a Howard Goodman Scholar Awardee and an MGH Research Scholar. D.T. is the recipient of the Brain Power for Israel Foundation grant and the Ellison Medical Foundation/AFAR Postdoctoral Fellowship. C.C. is supported by a Fellowship from the Fondazione Umberto Veronesi. C.S. is the recipient of a CDMRP/DoD Cancer Research Program Postdoctoral Fellowship. B.M.-P is the recipient of a postdoctoral fellowship from the Spanish Ministry of Education. We would like to thank Steve Jackson for the SIRT6-GFP and SIRT6-RFP plasmids and Laura Prickett-Rice and Kate Folz-Donahue for technical assistance with the FACS analysis.
PY - 2013/8/22
Y1 - 2013/8/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84882630603&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2013.06.018
DO - 10.1016/j.molcel.2013.06.018
M3 - Article
C2 - 23911928
AN - SCOPUS:84882630603
SN - 1097-2765
VL - 51
SP - 454
EP - 468
JO - Molecular Cell
JF - Molecular Cell
IS - 4
ER -
