Structural Basis for the Methylation State-Specific Recognition of Histone H4-K20 by 53BP1 and Crb2 in DNA Repair

Maria Victoria Botuyan, Joseph Lee, Irene M. Ward, Ja Eun Kim, James R. Thompson, Junjie Chen, Georges Mer

Research output: Contribution to journalArticlepeer-review

700 Scopus citations

Abstract

Histone lysine methylation has been linked to the recruitment of mammalian DNA repair factor 53BP1 and putative fission yeast homolog Crb2 to DNA double-strand breaks (DSBs), but how histone recognition is achieved has not been established. Here we demonstrate that this link occurs through direct binding of 53BP1 and Crb2 to histone H4. Using X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, we show that, despite low amino acid sequence conservation, both 53BP1 and Crb2 contain tandem tudor domains that interact with histone H4 specifically dimethylated at Lys20 (H4-K20me2). The structure of 53BP1/H4-K20me2 complex uncovers a unique five-residue 53BP1 binding cage, remarkably conserved in the structure of Crb2, that best accommodates a dimethyllysine but excludes a trimethyllysine, thus explaining the methylation state-specific recognition of H4-K20. This study reveals an evolutionarily conserved molecular mechanism of targeting DNA repair proteins to DSBs by direct recognition of H4-K20me2.

Original languageEnglish (US)
Pages (from-to)1361-1373
Number of pages13
JournalCell
Volume127
Issue number7
DOIs
StatePublished - Dec 29 2006
Externally publishedYes

Bibliographical note

Funding Information:
We acknowledge use of the X12C beamline of Brookhaven National Laboratory's National Synchrotron Light Source (NSLS) and 19ID beamline of Argonne National Laboratory's Advance Photon Source (APS). We thank S. Sclafani at NSLS and R. Alkire and Y. Kim at APS for their assistance with X-ray data collection, D. McCormick for advice on peptide syntheses, E. Wasielewski for assistance with figures, N. Juranic and S. Macura for assistance with NMR, and Y. Nominé for help with the calorimetry experiments. Use of Argonne National Laboratory Structural Biology Center beamlines at APS was supported by the U.S. Department of Energy under contract number W-31-109-ENG-38. This work was partially supported by an NIH grant (CA100109) and a DOD breast cancer Era of Hope Scholar Award (to J.C.). G.M. acknowledges partial support from the March of Dimes Basil O'Connor Starter Scholar Research Award and the Human Frontier Science Program Organization.

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