Non-canonical Bromodomain within DNA-PKcs Promotes DNA Damage Response and Radioresistance through Recognizing an IR-Induced Acetyl-Lysine on H2AX

作者：Wang, Li; Xie, Ling; Ramachandran, Srinivas; Lee, YuanYu; Yan, Zhen; Zhou, Li; Krajewski, Krzysztof; Liu, Feng; Zhu, Cheng; Chen, David J.; Strahl, Brian D.; Jin, Jian; Dokholyan, Nikolay V.; Chen, Xian^*

来源：Chemistry & Biology, 2015, 22(7): 849-861.

DOI：10.1016/j.chembiol.2015.05.014

• APOPTOSIS
• REPAIR
• ATM
• RECOGNITION
• CHECKPOINT
• CHROMATIN
• EXCHANGE
• SUBUNIT
• KINASE

Regulatory mechanisms underlying gamma H2AX induction and the associated cell fate decision during DNA damage response (DDR) remain obscure. Here, we discover a bromodomain (BRD)-like module in DNA-PKcs (DNA-PKcs-BRD) that specifically recognizes H2AX acetyl-lysine 5 (K5ac) for sequential induction of gH2AX and concurrent cell fate decision( s). First, top-down mass spectrometry of radiation-phenotypic, full-length H2AX revealed a radiation-inducible, K5ac-dependent induction of gamma H2AX. Combined approaches of sequence-structure modeling/docking, site-directed mutagenesis, and biochemical experiments illustrated that through docking on H2AX K5ac, this non-canonical BRD determines not only the H2AX-targeting activity of DNA-PKcs but also the over-activation of DNA-PKcs in radioresistant tumor cells, whereas a Kac antagonist, JQ1, was able to bind to DNA-PKcs-BRD, leading to re-sensitization of tumor cells to radiation. This study elucidates the mechanism underlying the H2AX-dependent regulation of DNA-PKcs in ionizing radiation-induced, differential DDR, and derives an unconventional, non-catalytic domain target in DNA-PKs for overcoming resistance during cancer radiotherapy.

• 出版日期2015-7-23
• 单位苏州大学; 郑州大学; 复旦大学