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Letters to Nature
Nature 432, 406-411 (18 November 2004) | doi:10.1038/nature03114; Received 6 July 2004; Accepted 15 October 2004; Published online 3 November 2004
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Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks
Yentram Huyen1,2, Omar Zgheib1,2, Richard A. DiTullio Jr1,2, Vassilis G. Gorgoulis1,4, Panayotis Zacharatos1,4, Tom J. Petty1,2, Emily A. Sheston1, Hestia S. Mellert1, Elena S. Stavridi1 & Thanos D. Halazonetis1,3
- Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA
- Biomedical Graduate Studies Program, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Department of Histology and Embryology, School of Medicine, University of Athens, Athens, 11527, Greece
Correspondence to: Thanos D. Halazonetis1,3 Email: halazonetis@wistar.upenn.edu
Structure coordinates have been deposited in the Protein Data Bank under the accession code 1XNI.
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.
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