Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks
Top Cited Papers
- 3 November 2004
- journal article
- research article
- Published by Springer Nature in Nature
- Vol. 432 (7015) , 406-411
- https://doi.org/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 sensor1,2,3,4,5. 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.Keywords
This publication has 28 references indexed in Scilit:
- Potential Role for 53BP1 in DNA End-joining Repair through Direct Interaction with DNAJournal of Biological Chemistry, 2003
- Accumulation of Checkpoint Protein 53BP1 at DNA Breaks Involves Its Binding to Phosphorylated Histone H2AXJournal of Biological Chemistry, 2003
- Combined Functional Genomic Maps of the C. elegans DNA Damage ResponseScience, 2002
- Tumor Suppressor P53 Binding Protein 1 (53bp1) Is Involved in DNA Damage–Signaling PathwaysThe Journal of cell biology, 2001
- Phosphorylation and Rapid Relocalization of 53BP1 to Nuclear Foci upon DNA DamageMolecular and Cellular Biology, 2001
- Negative Cell Cycle Regulation and DNA Damage-inducible Phosphorylation of the BRCT Protein 53BP1Journal of Biological Chemistry, 2001
- P53 Binding Protein 1 (53bp1) Is an Early Participant in the Cellular Response to DNA Double-Strand BreaksThe Journal of cell biology, 2000
- Damage and replication checkpoint control in fission yeast is ensured by interactions of Crb2, a protein with BRCT motif, with Cut5 and Chk1Genes & Development, 1997
- Isolation and characterization of the Schizosaccharomyces pombe rhp9 gene: a gene required for the DNA damage checkpoint but not the replication checkpointNucleic Acids Research, 1997
- The RAD9 Gene Controls the Cell Cycle Response to DNA Damage in Saccharomyces cerevisiaeScience, 1988