Double-strand break repair: 53BP1 comes into focus

• Published in: Nature reviews. Molecular cell biology Vol. 15; no. 1; pp. 7 - 18
• Main Authors: Panier, Stephanie, Boulton, Simon J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2014; Nature Publishing Group
• Subjects: 631/337/1427/2122; 631/337/1427/2190; 631/337/1427/2191; Animals; Antigens; Ataxia; Binding proteins; Biochemistry; Breast cancer; Cancer Research; Cell Biology; Cell cycle; Cellular control mechanisms; Chromatin - genetics; Chromatin - metabolism; Cyclin-dependent kinases; Deoxyribonucleic acid; Developmental Biology; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA End-Joining Repair; DNA Repair; Genetic aspects; Genetic research; Genomes; Histones - metabolism; Homeostasis; Humans; Identification and classification; Intracellular Signaling Peptides and Proteins - physiology; Kinases; Life Sciences; Medical research; Phosphorylation; Protein Transport; Proteins; review-article; Signal Transduction; Stem Cells; Tumor Suppressor p53-Binding Protein 1; Yeast
• ISSN: 1471-0072; 1471-0080
• DOI: 10.1038/nrm3719

Key Points 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. The function of 53BP1 in DNA double-strand break repair is multifaceted, and includes mediator and effector roles. New appreciation of how it is recruited to damaged chromatin, and how it exerts control on pathway choice, has cemented the central role of 53BP1 in genome stability maintenance. 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).