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

doi:10.1016/j.molcel.2013.06.018

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 journal › Article › peer-review

Abstract

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 language	American English
Pages (from-to)	454-468
Number of pages	15
Journal	Molecular Cell
Volume	51
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2013.06.018
State	Published - 22 Aug 2013
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.molcel.2013.06.018

Cite this

Toiber, D., Erdel, F., Bouazoune, K., Silberman, D. M., Zhong, L., Mulligan, P., Sebastian, C., Cosentino, C., Martinez-Pastor, B., Giacosa, S., D'Urso, A., Näär, A. M., Kingston, R., Rippe, K., & Mostoslavsky, R. (2013). SIRT6 Recruits SNF2H to DNA Break Sites, Preventing Genomic Instability Through Chromatin Remodeling. Molecular Cell, 51(4), 454-468. https://doi.org/10.1016/j.molcel.2013.06.018

@article{f41bcd4d24a9484fbb1e8de38bab34aa,

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

abstract = "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.",

author = "Debra Toiber and Fabian Erdel and Karim Bouazoune and Silberman, {Dafne M.} and Lei Zhong and Peter Mulligan and Carlos Sebastian and Claudia Cosentino and Barbara Martinez-Pastor and Sofia Giacosa and Agustina D'Urso and N{\"a}{\"a}r, {Anders M.} and Robert Kingston and Karsten Rippe and Raul Mostoslavsky",

note = "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.",

year = "2013",

month = aug,

day = "22",

doi = "10.1016/j.molcel.2013.06.018",

language = "American English",

volume = "51",

pages = "454--468",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "4",

}

Toiber, D, Erdel, F, Bouazoune, K, Silberman, DM, Zhong, L, Mulligan, P, Sebastian, C, Cosentino, C, Martinez-Pastor, B, Giacosa, S, D'Urso, A, Näär, AM, Kingston, R, Rippe, K & Mostoslavsky, R 2013, 'SIRT6 Recruits SNF2H to DNA Break Sites, Preventing Genomic Instability Through Chromatin Remodeling', Molecular Cell, vol. 51, no. 4, pp. 454-468. https://doi.org/10.1016/j.molcel.2013.06.018

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

SN - 1097-2765

VL - 51

SP - 454

EP - 468

JO - Molecular Cell

JF - Molecular Cell

IS - 4

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this