p53-binding protein 1 (53BP1) is a crucial component of DNA double-strand break (DSB) signalling and repair in mammalian cells.
It is recruited to DSBs downstream of RING finger 8 (RNF8)- and RNF168-dependent chromatin ubiquitylation. It reads a DSB-specific histone code that directly integrates ubiquitylation, methylation and acetylation signals at damaged chromatin.
Oligomerized 53BP1 binds directly to mono- and dimethylated Lys20 of histone 4 (H4K20me1 and H4K20me2) via its Tudor domain and to RNF168-ubiquitylated H2AK15 via its ubiquitylation-dependent recruitment (UDR) motif. The access of 53BP1 to mono- and dimethylated H4K20 and its recognition of ubiquitylated H2AK15 are modulated through several distinct mechanisms.
53BP1 is a key regulator of DSB repair pathway choice. During G1, it promotes non-homologous end-joining (NHEJ)-mediated DSB repair by antagonizing long-range DNA end-resection, which is essential for DSB repair via homologous recombination.
PTIP (PAX transactivation activation domain-interacting protein) and RIF1 (RAP1-interacting factor 1) are 53BP1 effector proteins during DSB repair pathway choice. They bind to ataxia-telangiectasia mutated (ATM)-phosphorylated Ser/Thr-Gln (S/T-Q) sites in the 53BP1 amino terminus.
During S–G2, breast cancer 1 (BRCA1) and its interacting partner CtBP-interacting protein (CtIP) counteract 53BP1–RIF1 and 53BP1–PTIP complexes to promote DNA end-resection and thus homologous recombination-mediated DSB repair.
Mechanistically, how 53BP1 and its cofactors block resection in G1 and how these activities are counteracted by BRCA1 to enable DSB repair by homologous recombination in S phase remains an open question in the field.
DNA double-strand break (DSB) signalling and repair is crucial to preserve genomic integrity and maintain cellular homeostasis. p53-binding protein 1 (53BP1) is an important regulator of the cellular response to DSBs that promotes the end-joining of distal DNA ends, which is induced during V(D)J and class switch recombination as well as during the fusion of deprotected telomeres. New insights have been gained into the mechanisms underlying the recruitment of 53BP1 to damaged chromatin and how 53BP1 promotes non-homologous end-joining-mediated DSB repair while preventing homologous recombination. From these studies, a model is emerging in which 53BP1 recruitment requires the direct recognition of a DSB-specific histone code and its influence on pathway choice is mediated by mutual antagonism with breast cancer 1 (BRCA1).
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The authors apologize to those whose important findings could not be mentioned as primary literature and/or cited owing to space constraints. They thank D. Durocher for critically reading the manuscript. S.P. is supported by a European Molecular Biology Organization (EMBO) long-term fellowship. S.J.B. holds the Royal Society Wolfson Research Merit Award. Work in the laboratory of S.J.B. is funded by Cancer Research UK and by a European Research Council advanced investigator grant (RecMitMei).
The authors declare no competing financial interests.
- DNA damage checkpoint
Signalling pathway that delays or arrests cell cycle progression in response to DNA damage.
Acts downstream of the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) kinases to recruit and/or activate additional DNA damage-responsive proteins.
Executes the functions of DNA damage response signalling, which include the activation of DNA damage checkpoints and DNA repair reactions.
- Tudor domains
Protein–protein interaction domains that were first identified in the Drosophila melanogaster protein Tudor and bind to methylated Arg or Lys residues.
- G2–M checkpoint
A type of DNA damage checkpoint that prevents cells with damaged genomes from entering into mitosis. It is predominantly mediated by the inhibition of CDC25 and cyclin-dependent kinase 1 (CDK1) by the effector kinases checkpoint kinase 1 (CHK1) and CHK2, and by p53.
- V(D)J recombination
A type of programmed genome rearrangement in maturing T and B lymphocytes during which variable (V), diversity (D) and joining (J) immunoglobulin gene segments are randomly combined by induction of DNA double-strand breaks, and repaired by non-homologous end-joining to generate antibodies with different antigen specificities.
- Class switch recombination
(CSR). Genome rearrangements in activated B lymphocytes that promote the generation of different antibody isotypes with the same antigen specificity. It involves the programmed formation and repair of DNA double-strand breaks within the switch regions between different antibody heavy chain gene segments.
- E3 ubiquitin ligases
Key enzymes in the ubiquitylation reaction that is required for the attachment of ubiquitin moieties to a substrate protein. They provide substrate specificity to a multistep reaction that initially involves an E1 activating enzyme probably followed by E2 conjugating enzymes and then E3 ubiquitin ligases.
- Valosin-containing protein
(VCP). AAA+ type ATPase that is important for the ATP-dependent unfolding of proteins and the disassembly of ubiquitylated protein–protein and protein–DNA complexes.
- Lys48-linked polyubiquitin
Type of ubiquitin chain that targets proteins for degradation by the 26S proteasome.
Large multisubunit protein complex that caps chromosome ends and prevents illegitimate DNA repair reactions.
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Panier, S., Boulton, S. Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol 15, 7–18 (2014). https://doi.org/10.1038/nrm3719
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