Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks

Yentram Huyen; Omar Zgheib; Richard A Ditullio Jr; Vassilis G Gorgoulis; Panayotis Zacharatos; Tom J Petty; Emily A Sheston; Hestia S Mellert; Elena S Stavridi; Thanos D Halazonetis

doi:10.1038/nature03114

Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks

Nature. 2004 Nov 18;432(7015):406-11. doi: 10.1038/nature03114. Epub 2004 Nov 3.

Authors

Yentram Huyen¹, Omar Zgheib, Richard A Ditullio Jr, Vassilis G Gorgoulis, Panayotis Zacharatos, Tom J Petty, Emily A Sheston, Hestia S Mellert, Elena S Stavridi, Thanos D Halazonetis

Affiliation

¹ Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA.

PMID: 15525939
DOI: 10.1038/nature03114

Abstract

The mechanisms by which eukaryotic cells sense DNA double-strand breaks (DSBs) in order to initiate checkpoint responses are poorly understood. 53BP1 is a conserved checkpoint protein with properties of a DNA DSB sensor. Here, we solved the structure of the domain of 53BP1 that recruits it to sites of DSBs. This domain consists of two tandem tudor folds with a deep pocket at their interface formed by residues conserved in the budding yeast Rad9 and fission yeast Rhp9/Crb2 orthologues. In vitro, the 53BP1 tandem tudor domain bound histone H3 methylated on Lys 79 using residues that form the walls of the pocket; these residues were also required for recruitment of 53BP1 to DSBs. Suppression of DOT1L, the enzyme that methylates Lys 79 of histone H3, also inhibited recruitment of 53BP1 to DSBs. Because methylation of histone H3 Lys 79 was unaltered in response to DNA damage, we propose that 53BP1 senses DSBs indirectly through changes in higher-order chromatin structure that expose the 53BP1 binding site.

Publication types

Research Support, U.S. Gov't, P.H.S.

MeSH terms

Amino Acid Sequence
Binding Sites
Cell Line, Tumor
Chromatin / chemistry
Chromatin / metabolism
Conserved Sequence
Cross-Linking Reagents / chemistry
DNA / chemistry
DNA / genetics
DNA / metabolism*
DNA Damage*
Histone-Lysine N-Methyltransferase
Histones / chemistry*
Histones / metabolism*
Humans
Intracellular Signaling Peptides and Proteins / chemistry
Intracellular Signaling Peptides and Proteins / metabolism*
Lysine / metabolism*
Methylation
Methyltransferases / deficiency
Methyltransferases / genetics
Methyltransferases / metabolism
Models, Molecular
Molecular Sequence Data
Phosphoproteins / chemistry
Phosphoproteins / metabolism*
Protein Binding
Protein Structure, Tertiary
Tumor Suppressor p53-Binding Protein 1

Substances

Chromatin
Cross-Linking Reagents
Histones
Intracellular Signaling Peptides and Proteins
Phosphoproteins
TP53BP1 protein, human
Tumor Suppressor p53-Binding Protein 1
DNA
DOT1L protein, human
Methyltransferases
Histone-Lysine N-Methyltransferase
Lysine

Associated data

PDB/1XNI