Loss of functional BRCA1 protein leads to defects in DNA double-strand break (DSB) repair by homologous recombination (HR) and renders cells hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors used to treat BRCA1/2-deficient cancers. However, upon chronic treatment of BRCA1-mutant cells with PARP inhibitors, resistant clones can arise via several mechanisms, including loss of 53BP1 or its downstream co-factors. Defects in the 53BP1 axis partially restore the ability of a BRCA1-deficient cell to form RAD51 filaments at resected DSBs in a PALB2- and BRCA2-dependent manner, and thereby repair DSBs by HR. Here we show that depleting 53BP1 in BRCA1-null cells restores PALB2 accrual at resected DSBs. Moreover, we demonstrate that PALB2 DSB recruitment in BRCA1/53BP1-deficient cells is mediated by an interaction between PALB2's chromatin associated motif (ChAM) and the nucleosome acidic patch region, which in 53BP1-expressing cells is bound by 53BP1's ubiquitin-directed recruitment (UDR) domain.
Conflict of interest statement
S.P.J. declares that he is founder and shareholder of Mission Therapeutics Ltd, Adrestia Therapeutics Ltd, Ahren Innovation Capital LLP, and Carrick Therapeutics Ltd. The other authors declare no competing interests.
The ASCIZ-DYNLL1 Axis Promotes 53BP1-dependent Non-Homologous End Joining and PARP Inhibitor SensitivityJR Becker et al. Nat Commun 9 (1), 5406. PMID 30559443.53BP1 controls a specialized non-homologous end joining (NHEJ) pathway that is essential for adaptive immunity, yet oncogenic in BRCA1 mutant cancers. Intra-chromosomal D …
RING Finger Nuclear Factor RNF168 Is Important for Defects in Homologous Recombination Caused by Loss of the Breast Cancer Susceptibility Factor BRCA1MC Muñoz et al. J Biol Chem 287 (48), 40618-28. PMID 23055523.RNF168 is important for HR defects caused by BRCA1 loss.
BRCA1 Haploinsufficiency Is Masked by RNF168-Mediated Chromatin UbiquitylationD Zong et al. Mol Cell 73 (6), 1267-1281.e7. PMID 30704900.BRCA1 functions at two distinct steps during homologous recombination (HR). Initially, it promotes DNA end resection, and subsequently it recruits the PALB2 and BRCA2 med …
Regulation of Repair Pathway Choice at Two-Ended DNA Double-Strand BreaksA Shibata. Mutat Res 803-805, 51-55. PMID 28781144. - ReviewA DNA double-strand break (DSB) is considered to be a critical DNA lesion because its misrepair can cause severe mutations, such as deletions or chromosomal translocation …
BRCA1, PARP, and 53BP1: Conditional Synthetic Lethality and Synthetic ViabilityA Aly et al. J Mol Cell Biol 3 (1), 66-74. PMID 21278454. - ReviewBRCA1 plays a critical role in the regulation of homologous recombination (HR)-mediated DNA double-strand break repair. BRCA1-deficient cancers have evolved to tolerate l …