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Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair

Maria Victoria Botuyan1, Joseph Lee, Irene M Ward

  • 1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

Cell
|December 28, 2006
PubMed

Insights

DNA repair factors 53BP1 and Crb2 bind directly to histone H4 dimethylated at Lys20 (H4-K20me2). This interaction, mediated by tandem tudor domains, is crucial for targeting DNA repair proteins to double-strand breaks (DSBs).

Area of Science:

  • Molecular Biology
  • Epigenetics
  • DNA Repair

Background:

  • Histone lysine methylation is implicated in recruiting DNA repair factors like 53BP1 and Crb2 to DNA double-strand breaks (DSBs).
  • The precise mechanism of histone recognition by these factors remained uncharacterized.

Purpose of the Study:

  • To elucidate the molecular mechanism by which 53BP1 and Crb2 recognize histone modifications at DSBs.
  • To determine how histone H4 methylation specifically recruits DNA repair proteins.

Main Methods:

  • X-ray crystallography
  • Nuclear Magnetic Resonance (NMR) spectroscopy
  • Biochemical binding assays

Main Results:

  • Direct binding of 53BP1 and Crb2 to histone H4, specifically dimethylated at Lys20 (H4-K20me2).
  • Tandem tudor domains in 53BP1 and Crb2 recognize H4-K20me2 through a conserved binding cage.
  • The binding cage accommodates dimethyllysine but excludes trimethyllysine, explaining methylation state specificity.

Conclusions:

  • A conserved molecular mechanism involving direct recognition of H4-K20me2 targets DNA repair proteins to DSBs.
  • This finding reveals evolutionary conservation in the epigenetic regulation of DNA repair pathways.

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