Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA non-homologous end-joining

By K. Miller, J. Tjeertes, J. Coates, G. Legube, S. Polo, S. Britton, Stephen P. Jackson. Nature Structural &Molecular Biology, 2010

643 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/382323a67d6c232a2d0b41616dbf5f9dbc3a767c

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

1. Stephen P. Jackson
2. J. Bartek
3. S. Polo
4. J. Lukas
5. C. Lukas
6. E. Seto
7. Raphaël Rodriguez
8. Yosef Shiloh

Citations in the corpus

• HDACs and HDAC Inhibitors in Cancer Development and Therapy (2016, positive): “HDAC1 and HDAC2 are recruited to DNA-damage sites to deacetylate histones H3K56 and H4K16, and facilitate nonhomologous end-joining (NHEJ) (Miller et al. 2010), suggesting a direct role for these two enzymes during DNA replication and double-strand break (DSB) repair.”
• Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. (2011, background): “…been observed at DSB sites in mammalian cells (Kao et al. 2003; Murr et al. 2006; O’Hagan et al. 2008; Oberdoerffer et al. 2008; Kaidi et al. 2010; Miller et al. 2010), and several studies have suggested roles for histone acetylation in regulating the dynamics of DDR factors in the vicinity of…”
• Small molecule-induced DNA damage identifies alternative DNA structures in human genes (2012, positive): “MRC-5–SV40 cells were analyzed essentially as previously describe”
• DNA damage and its links to neurodegeneration (2014, neutral): “However, recent studies in several systems, including postmitotic neurons, have unveiled the roles of HDACs and chromatin compaction in the early phase of DNA repair (Dobbin et al., 2013; Miller et al., 2010; O’Hagan et al., 2008).”
• More than just a focus: The chromatin response to DNA damage and its role in genome integrity maintenance (2011, background): “DNA breaks also trigger local accumulation of at least two histone deacetylases, HDAC1 and HDAC2, which is accompanied by deacetylation of Lys 56 of histone H3 (H3K56) and Lys 16 of histone H4 (H4K16”