Mechanistic links between ATM and histone methylation codes during DNA repair

Ye Xu, Chang Xu, Brendan D. Price

Research output: Chapter in Book/Report/Conference proceedingChapter

12 Scopus citations

Abstract

The ataxia telangiectasia-mutated (ATM) protein kinase is the master regulator of the DNA double-strand break (DSB) repair pathway. The activation of ATM involves its recruitment to the DSB through interaction with the mre11-rad50-nbs1 complex, followed by the acetylation of ATM by the Tip60 acetyltransferase. This acetylation of ATM within its regulatory domain is essential for activating ATM's kinase activity. Further work has now revealed that Tip60 is activated through direct interaction between Tip60's chromodomain and histone H3 trimethylated on lysine 9 (H3K9me3). The loading of Tip60 onto the chromatin at DSBs therefore represents the primary mechanism for activation of Tip60's acetyltransferase activity in response to DNA damage. The ability of H3K9me3 at DSBs to regulate the activity of Tip60 and the subsequent activation of ATM emphasizes the crucial role played by chromatin architecture in regulating DSB repair. Further, histone methylation and chromatin structure are disrupted in human cancers, implying that altered chromatin structure in tumor cells may impact DSB repair, increasing genomic instability and contributing to the progression of cancer.

Original languageEnglish (US)
Title of host publicationProgress in Molecular Biology and Translational Science
PublisherElsevier B.V.
Pages263-288
Number of pages26
DOIs
StatePublished - 2012
Externally publishedYes

Publication series

NameProgress in Molecular Biology and Translational Science
Volume110
ISSN (Print)1877-1173

Keywords

  • Acetylation
  • ATM
  • Chromodomain
  • DNA repair
  • DSBs
  • H3K9me3
  • Histone methylation
  • Tip60

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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  • Cite this

    Xu, Y., Xu, C., & Price, B. D. (2012). Mechanistic links between ATM and histone methylation codes during DNA repair. In Progress in Molecular Biology and Translational Science (pp. 263-288). (Progress in Molecular Biology and Translational Science; Vol. 110). Elsevier B.V.. https://doi.org/10.1016/B978-0-12-387665-2.00010-9