人类 HDAC1 和 HDAC2 在 DNA 损伤反应中发挥作用，促进 DNA 非同源末端连接。
Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining.
机构信息
The Gurdon Institute, University of Cambridge, Cambridge, UK.
出版信息
Nat Struct Mol Biol. 2010 Sep;17(9):1144-51. doi: 10.1038/nsmb.1899. Epub 2010 Aug 29.
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.
摘要
DNA 双链断裂 (DSB) 修复发生在染色质中，并可被染色质修饰酶调节。在这里，我们鉴定出相关的人类组蛋白去乙酰化酶 HDAC1 和 HDAC2 是 DNA 损伤反应的两个参与者。我们表明，组蛋白 H3 赖氨酸 56 (H3K56) 的乙酰化受 HDAC1 和 HDAC2 调节，HDAC1 和 HDAC2 被迅速募集到 DNA 损伤部位，以促进 H3K56 的低乙酰化。此外，HDAC1 和 2 耗尽的细胞对 DNA 损伤剂敏感，并表现出持续的 DNA 损伤信号，这些表型反映了 DSB 修复缺陷，特别是非同源末端连接 (NHEJ)。总的来说，这些结果表明，HDAC1 和 HDAC2 通过促进 DSB 修复在 DNA 损伤反应中发挥作用，从而为正在开发作为癌症治疗方法的 HDAC 抑制剂的放射增敏作用提供了重要的见解。
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