Mechanistic links between ATM and histone methylation codes during DNA repair

Ye Xu, Chang Xu, Brendan D. Price

Research output: Contribution to journalArticle

12 Citations (Scopus)

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)
Pages (from-to)263-288
Number of pages26
JournalProgress in Molecular Biology and Translational Science
Volume110
DOIs
StatePublished - 2012
Externally publishedYes

Fingerprint

Histone Code
Ataxia Telangiectasia
DNA Repair
Methylation
Chromatin
Acetyltransferases
Acetylation
Histones
Ataxia Telangiectasia Mutated Proteins
Neoplasms
Double-Stranded DNA Breaks
Genomic Instability
Protein Kinases
Lysine
DNA Damage
Phosphotransferases

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Molecular Medicine

Cite this

Mechanistic links between ATM and histone methylation codes during DNA repair. / Xu, Ye; Xu, Chang; Price, Brendan D.

In: Progress in Molecular Biology and Translational Science, Vol. 110, 2012, p. 263-288.

Research output: Contribution to journalArticle

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