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PMID: 17190600 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

Cell ·Vol. 127 ·No. 7 ·2006-12-29 ·Pages 1361-73

Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, Chen J, Mer G

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.

MeSH Terms
Amino Acid Sequence Binding Sites Carrier Proteins/chemistry,genetics,metabolism Chromatin/chemistry,metabolism Conserved Sequence Crystallography, X-Ray DNA Breaks, Double-Stranded DNA Repair Histones/chemistry,metabolism Humans Intracellular Signaling Peptides and Proteins/chemistry,metabolism Lysine Magnetic Resonance Spectroscopy Membrane Proteins/chemistry,genetics,metabolism Methylation Molecular Sequence Data Mutation Phosphoproteins/chemistry,metabolism Protein Structure, Tertiary Tandem Repeat Sequences Tumor Suppressor p53-Binding Protein 1
Chemicals
CRB2 protein, human Carrier Proteins Chromatin Histones Intracellular Signaling Peptides and Proteins Membrane Proteins Phosphoproteins TP53BP1 protein, human Tumor Suppressor p53-Binding Protein 1 Lysine
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Botuyan Maria Victoria
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Lee Joseph
Ward Irene M
Kim Ja-Eun
Thompson James R
Chen Junjie
Mer Georges
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
0092-8674
DOI
10.1016/j.cell.2006.10.043
Published
2006-12-29
Pages
1361-73
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC1804291
Subset
IM
Grants
NCI NIH HHS · R01 CA100109 · United States
NCI NIH HHS · R01 CA109449 · United States
NCI NIH HHS · CA100109 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2006.10.043 PMC Full Text View journal details
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