53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks

By S. Bunting, E. Callen, N. Wong, Hua-Tang Chen, F. Polato, Amanda L. Gunn, Anne Bothmer, N. Feldhahn, O. Fernández-Capetillo, Liu Cao and 6 more. Cell, 2010

1,669 citations recorded by the source corpus.

SUMMARY Defective DNA repair by homologous recombination (HR) is thought to be a major contributor to tumorigenesis in individuals carrying Brca1 mutations. Here we show that DNA breaks in Brca1-deficient cells are aberrantly joined into complex chromosome rearrangements by a process dependent on the non-homologous end joining (NHEJ) factors, 53BP1 and DNA Ligase 4. Loss of 53BP1 alleviates hypersensitivity of Brca1 mutant cells to PARP inhibition and restores error-free repair by HR. Mechanistically, 53BP1 deletion promotes ATM-dependent processing of broken DNA ends to produce recombinogenic single-stranded DNA competent for HR. In contrast, Lig4 deficiency does not rescue the HR defect in Brca1 mutant cells, but prevents the joining of chromatid breaks into chromosome rearrangements. Our results illustrate that HR and NHEJ compete to process DNA breaks that arise during DNA replication, and that shifting the balance between these pathways can be exploited to selectively protect or kill cells harboring Brca1 mutations.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/1bf81cebfe19aa034c8496a4b52e13a2cef4f2ea

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Citations in the corpus

A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice. (2013, background): “Finally, it is important to evaluate the results presented herein in relation to BRCA1-deficient malignancies since the lethality, tumorigenesis, and PARP inhibitor sensitivity conferred by M BRCA1 deficiency can be suppressed by 53BP1 deletion (Bouwman et al., 2010; Bunting et al., 2010).”
Playing the end game: DNA double-strand break repair pathway choice. (2012, background): “On the other hand, defects associated with Brca1 deficiency are not rescued by DNA ligase IV (Lig4) deletion, and are only partially alleviated by chemical inhibition of DNA-PKcs (Bunting et al., 2010; Patel et al., 2011).”
Laying a trap to kill cancer cells: PARP inhibitors and their mechanisms of action (2016, background): “The clinical relevance of reactivating mutations of BRCA1 (56), up-regulation of the DNA end resection protein CTIP (57) to reactivate HRR, and inactivation of 53BP1 (58) to suppress nonhomologous end-joining (NHEJ), which competes with HRR, still needs to be established.”
Homologous recombination and human health: the roles of BRCA1, BRCA2 and associated proteins (2015, background): “The rescue of certain HR mutants with combined NHEJ deficiency also speaks to the competition between pathways (see below) (Bouwman et al. 2010; Bunting et al. 2010).”
The DNA damage response and cancer therapy (2012, background): “and the loss of TP53BP1 (a DDR protein) in BRCA1 -deficient cells, suggesting that these mechanisms should also be assessed in clinical biopsie”
53BP1 is a reader of the DNA damage-induced H2A Lys15 ubiquitin mark (2013, methodology): “The retroviral vector pMX-53BP1 (1-1711) and its D1521R derivative were gifts of André Nussenzweig9.”
Mechanisms of DNA damage, repair and mutagenesis (2017, background): “each other and 53BP1 depletion rescues embryonic lethality of BRCA1 null mice [Xie et al., 2007; Cao et al., 2009; Bunting et al., 2010].”
The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings (2011, background): “Furthermore, recent findings showing that loss of 53BP1 in BRCA1mutant cells alleviates hypersensitivity to PARP inhibitors and restores HR suggest a role for BRCA1 and 53BP1 in regulating the choice between HR and NHEJ pathways for DNA repair (Bouwman et al., 2010; Bunting et al., 2010).”
Repair of strand breaks by homologous recombination. (2013, background): “Evidence indicates that 53bp1 disruption restores HR in BRCA1-deficient cells, likely by relieving 53BP1 inhibition of end resection at DSBs (Bouwman et al. 2010; Bunting et al. 2010).”