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

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

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Summary Regulatory mechanisms underlying γH2AX 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 γH2AX 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 γH2AX. 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.

Original languageEnglish (US)
Article number3066
Pages (from-to)849-861
Number of pages13
JournalChemistry and Biology
Volume22
Issue number7
DOIs
StatePublished - Jan 26 2015

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

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    Wang, L., Xie, L., Ramachandran, S., Lee, Y., Yan, Z., Zhou, L., Krajewski, K., Liu, F., Zhu, C., Chen, D. J., Strahl, B. D., Jin, J., Dokholyan, N. V., & Chen, X. (2015). Non-canonical Bromodomain within DNA-PKcs Promotes DNA Damage Response and Radioresistance through Recognizing an IR-Induced Acetyl-Lysine on H2AX. Chemistry and Biology, 22(7), 849-861. [3066]. https://doi.org/10.1016/j.chembiol.2015.05.014