Human HDAC1 and HDAC2 Function in the DNA-damage Response to Promote DNA Nonhomologous End-joining

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2010 Aug 31

PMID 20802485

Citations 364

Authors

Kyle M Miller

Jorrit V Tjeertes

Julia Coates

Gaelle Legube

Sophie E Polo

Sebastien Britton

Stephen P Jackson

Affiliations

Soon will be listed here.

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.

Citing Articles

HIV-1 Vpr drives epigenetic remodeling to enhance virus transcription and latency reactivation.

Saladino N, Leavitt E, Wong H, Ji J, Ebrahimi D, Salamango D bioRxiv. 2025; .

PMID: 39975144 PMC: 11838372. DOI: 10.1101/2025.01.31.635859.

Genomic hallmarks of endocrine therapy resistance in ER/PR+HER2- breast tumours.

Ghosh A, Chaubal R, Das C, Parab P, Das S, Maitra A Commun Biol. 2025; 8(1):207.

PMID: 39930151 PMC: 11811163. DOI: 10.1038/s42003-025-07606-x.

Pan-cancer analysis of the transcriptional expression of histone acetylation enzymes in solid tumors defines a new classification scheme for gliomas.

Zhang J, Li L, Tang A, Wang C, Wang Y, Hu Y Front Immunol. 2025; 15:1523034.

PMID: 39906742 PMC: 11790639. DOI: 10.3389/fimmu.2024.1523034.

A phase I study of MLN4924 and belinostat in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome.

Maher K, Shafer D, Schaar D, Bandyopadhyay D, Deng X, Wright J Cancer Chemother Pharmacol. 2025; 95(1):24.

PMID: 39821392 PMC: 11742280. DOI: 10.1007/s00280-024-04742-9.

Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.

Likasitwatanakul P, Li Z, Doan P, Spisak S, Raghawan A, Liu Q bioRxiv. 2024; .

PMID: 39713466 PMC: 11661112. DOI: 10.1101/2024.12.06.626451.

References

Mahaney B, Meek K, Lees-Miller S . Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. Biochem J. 2009; 417(3):639-50. PMC: 2975036. DOI: 10.1042/BJ20080413. View

Haigis M, Sinclair D . Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010; 5:253-95. PMC: 2866163. DOI: 10.1146/annurev.pathol.4.110807.092250. View

Huen M, Grant R, Manke I, Minn K, Yu X, Yaffe M . RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell. 2007; 131(5):901-14. PMC: 2149842. DOI: 10.1016/j.cell.2007.09.041. View

Luo J, Nikolaev A, Imai S, Chen D, Su F, SHILOH A . Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001; 107(2):137-48. DOI: 10.1016/s0092-8674(01)00524-4. View

Xie W, Song C, Young N, Sperling A, Xu F, Sridharan R . Histone h3 lysine 56 acetylation is linked to the core transcriptional network in human embryonic stem cells. Mol Cell. 2009; 33(4):417-27. PMC: 2671231. DOI: 10.1016/j.molcel.2009.02.004. View

Bandyopadhyay D, Okan N, Bales E, Nascimento L, Cole P, Medrano E . Down-regulation of p300/CBP histone acetyltransferase activates a senescence checkpoint in human melanocytes. Cancer Res. 2002; 62(21):6231-9. View

Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C . RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell. 2007; 131(5):887-900. DOI: 10.1016/j.cell.2007.09.040. View

Doil C, Mailand N, Bekker-Jensen S, Menard P, Larsen D, Pepperkok R . RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell. 2009; 136(3):435-46. DOI: 10.1016/j.cell.2008.12.041. View

Murr R, Loizou J, Yang Y, Cuenin C, Li H, Wang Z . Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nat Cell Biol. 2005; 8(1):91-9. DOI: 10.1038/ncb1343. View

10.

Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N . Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006; 444(7119):633-7. DOI: 10.1038/nature05268. View

11.

Bird A, Yu D, Pray-Grant M, Qiu Q, Harmon K, Megee P . Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair. Nature. 2002; 419(6905):411-5. DOI: 10.1038/nature01035. View

12.

Iacovoni J, Caron P, Lassadi I, Nicolas E, Massip L, Trouche D . High-resolution profiling of gammaH2AX around DNA double strand breaks in the mammalian genome. EMBO J. 2010; 29(8):1446-57. PMC: 2868577. DOI: 10.1038/emboj.2010.38. View

13.

Miller K, Maas N, Toczyski D . Taking it off: regulation of H3 K56 acetylation by Hst3 and Hst4. Cell Cycle. 2006; 5(22):2561-5. DOI: 10.4161/cc.5.22.3501. View

14.

Li B, Carey M, Workman J . The role of chromatin during transcription. Cell. 2007; 128(4):707-19. DOI: 10.1016/j.cell.2007.01.015. View

15.

Kouzarides T . Chromatin modifications and their function. Cell. 2007; 128(4):693-705. DOI: 10.1016/j.cell.2007.02.005. View

16.

Camphausen K, Tofilon P . Inhibition of histone deacetylation: a strategy for tumor radiosensitization. J Clin Oncol. 2007; 25(26):4051-6. DOI: 10.1200/JCO.2007.11.6202. View

17.

dAdda di Fagagna F . Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008; 8(7):512-22. DOI: 10.1038/nrc2440. View

18.

Goodarzi A, Noon A, Deckbar D, Ziv Y, Shiloh Y, Lobrich M . ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol Cell. 2008; 31(2):167-77. DOI: 10.1016/j.molcel.2008.05.017. View

19.

Di Micco R, Fumagalli M, Cicalese A, Piccinin S, Gasparini P, Luise C . Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006; 444(7119):638-42. DOI: 10.1038/nature05327. View

20.

Wang Z, Zang C, Cui K, Schones D, Barski A, Peng W . Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell. 2009; 138(5):1019-31. PMC: 2750862. DOI: 10.1016/j.cell.2009.06.049. View