Histone deacetylase regulation of ATM-mediated DNA damage signaling.
Histone deacetylase regulation of ATM-mediated DNA damage signaling.
复制标题
DOI：
10.1158/1535-7163.mct-12-1242
复制
发表时间：
2013-10
影响因子：
5.7
通讯作者：
Munster PN
中科院分区：
文献类型：
--
作者：
Thurn KT;Thomas S;Raha P;Qureshi I;Munster PN
Ataxia-telangiectasia mutated (ATM) is a major regulator of the DNA damage response. ATM promotes the activation of BRCA1, CHK2, and p53 leading to the induction of response genes such as CDKN1A (p21), GADD45A and RRM2B that promote cell cycle arrest and DNA repair. The up-regulation of these response genes may contribute to resistance of cancer cells to genotoxic therapies. Here we show that histone deacetylases (HDACs) play a major role in mitigating the response of the ATM pathway to DNA damage. HDAC inhibition decreased ATM activation and expression, and attenuated the activation of p53 in vitro and in vivo. Select depletion of HDAC1 and HDAC2 was sufficient to modulate ATM activation, reduce GADD45A and RRM2B induction, and increase sensitivity to DNA strand breaks. The regulation of ATM by HDAC enzymes therefore suggests a vital role for HDAC1 and HDAC2 in the DNA damage response, and the potential use of the ATM pathway as a pharmacodynamic marker for combination therapies involving HDAC inhibitors.
