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PMID: 23760478 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark.

Nature ·Vol. 499 ·No. 7456 ·2013-07-04 ·Pages 50-4

Fradet-Turcotte A, Canny MD, Escribano-Díaz C, Orthwein A, Leung CC, Huang H, Landry MC, Kitevski-LeBlanc J, Noordermeer SM, Sicheri F, Durocher D

Abstract

53BP1 (also called TP53BP1) is a chromatin-associated factor that promotes immunoglobulin class switching and DNA double-strand-break (DSB) repair by non-homologous end joining. To accomplish its function in DNA repair, 53BP1 accumulates at DSB sites downstream of the RNF168 ubiquitin ligase. How ubiquitin recruits 53BP1 to break sites remains unknown as its relocalization involves recognition of histone H4 Lys 20 (H4K20) methylation by its Tudor domain. Here we elucidate how vertebrate 53BP1 is recruited to the chromatin that flanks DSB sites. We show that 53BP1 recognizes mononucleosomes containing dimethylated H4K20 (H4K20me2) and H2A ubiquitinated on Lys 15 (H2AK15ub), the latter being a product of RNF168 action on chromatin. 53BP1 binds to nucleosomes minimally as a dimer using its previously characterized methyl-lysine-binding Tudor domain and a carboxy-terminal extension, termed the ubiquitination-dependent recruitment (UDR) motif, which interacts with the epitope formed by H2AK15ub and its surrounding residues on the H2A tail. 53BP1 is therefore a bivalent histone modification reader that recognizes a histone 'code' produced by DSB signalling.

MeSH Terms
Amino Acid Motifs Amino Acid Sequence Animals Cell Cycle Proteins/chemistry,metabolism Cell Line Chromosomal Proteins, Non-Histone/chemistry,deficiency,genetics DNA Breaks, Double-Stranded DNA Damage DNA-Binding Proteins/chemistry,deficiency,genetics Female Histones/chemistry,metabolism Humans Intracellular Signaling Peptides and Proteins/chemistry,deficiency,genetics,metabolism Lysine/metabolism Male Mice Molecular Sequence Data Mutant Proteins/chemistry,metabolism Nuclear Proteins/chemistry,metabolism Nucleosomes/chemistry,metabolism Protein Binding Protein Structure, Tertiary Schizosaccharomyces Schizosaccharomyces pombe Proteins/chemistry,metabolism Signal Transduction Tumor Suppressor p53-Binding Protein 1 Ubiquitin/metabolism Ubiquitination
Chemicals
Cell Cycle Proteins Chromosomal Proteins, Non-Histone Crb2 protein, S pombe DNA-Binding Proteins Histones Intracellular Signaling Peptides and Proteins Mutant Proteins Nuclear Proteins Nucleosomes Schizosaccharomyces pombe Proteins Trp53bp1 protein, mouse Tumor Suppressor p53-Binding Protein 1 Ubiquitin Lysine
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Fradet-Turcotte Amélie
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
Canny Marella D
Escribano-Díaz Cristina
Orthwein Alexandre
Leung Charles C Y
Huang Hao
Landry Marie-Claude
Kitevski-LeBlanc Julianne
Noordermeer Sylvie M
Sicheri Frank
Durocher Daniel
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature12318
Published
2013-07-04
Epub
2013-00-12
Pages
50-4
Language
English
Region
England
NLM ID
0410462
PMCID
PMC3955401
Subset
IM
Grants
Canadian Institutes of Health Research · 84297-1 · Canada
Canadian Institutes of Health Research · 84297-2 · Canada
CIHR · MOP84297 · Canada
External Links
PubMed source DOI: 10.1038/nature12318 PMC Full Text View journal details
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