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PMID: 20802485 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining.

Nature structural & molecular biology ·Vol. 17 ·No. 9 ·2010-09-00 ·Pages 1144-51

Miller KM, Tjeertes JV, Coates J, Legube G, Polo SE, Britton S, Jackson SP

Abstract

DNA double-strand break (DSB) repair occurs within chromatin and can be modulated by chromatin-modifying enzymes. Here we identify the related human histone deacetylases HDAC1 and HDAC2 as two participants in the DNA-damage response. We show that acetylation of histone H3 Lys56 (H3K56) was regulated by HDAC1 and HDAC2 and that HDAC1 and HDAC2 were rapidly recruited to DNA-damage sites to promote hypoacetylation of H3K56. Furthermore, HDAC1- and 2-depleted cells were hypersensitive to DNA-damaging agents and showed sustained DNA-damage signaling, phenotypes that reflect defective DSB repair, particularly by nonhomologous end-joining (NHEJ). Collectively, these results show that HDAC1 and HDAC2 function in the DNA-damage response by promoting DSB repair and thus provide important insights into the radio-sensitizing effects of HDAC inhibitors that are being developed as cancer therapies.

MeSH Terms
Cell Line, Tumor DNA Breaks, Double-Stranded DNA Repair Histone Deacetylase 1/genetics,metabolism Histone Deacetylase 2/genetics,metabolism Histones/metabolism Humans RNA, Small Interfering
Chemicals
Histones RNA, Small Interfering HDAC1 protein, human HDAC2 protein, human Histone Deacetylase 1 Histone Deacetylase 2
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Miller Kyle M
The Gurdon Institute, University of Cambridge, Cambridge, UK.
Tjeertes Jorrit V
Coates Julia
Legube Gaëlle
Polo Sophie E
Britton Sébastien
Jackson Stephen P
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.1899
Published
2010-09-00
Epub
2010-00-29
Pages
1144-51
Language
English
Region
United States
NLM ID
101186374
PMCID
PMC3018776
Subset
IM
Grants
Cancer Research UK · 11224 · United Kingdom
Biotechnology and Biological Sciences Research Council · United Kingdom
Cancer Research UK · A5290 · United Kingdom
Wellcome Trust · 086861/Z/08/Z · United Kingdom
Wellcome Trust · 086861 · United Kingdom
External Links
PubMed source DOI: 10.1038/nsmb.1899 PMC Full Text View journal details
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