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. 2025 Aug 7;85(15):2824-2838.e8.
doi: 10.1016/j.molcel.2025.07.003. Epub 2025 Jul 31.

PALB2 and 53BP1 govern post-resection homologous recombination DNA repair

Yifan Wang  1 , Yan Coulombe  2 , Wei-Ting Yueh  1 , Gregory D Conway  1 , Larissa Milano  2 , David J Glass  3 , Mélissa Thomas  2 , Amélie Rodrigue  2 , Joseph Nacson  1 , Dongbo Lu  4 , Andrea J Bernhardy  1 , Robert G Betsch  1 , Alyssa I Russo  1 , Gamal A Elfar  1 , Kathy Q Cai  1 , Joseph R Testa  1 , Mark Andrake  1 , Roland Dunbrack  1 , Gaorav P Gupta  4 , Bing Xia  5 , Eloise Dray  6 , Jean-Yves Masson  7 , Neil Johnson  8
Affiliations

PALB2 and 53BP1 govern post-resection homologous recombination DNA repair

Yifan Wang et al. Mol Cell. .

Abstract

Homologous recombination (HR) requires the resection of DNA breaks and RAD51 filament formation. Protein complexes that control end resection have been characterized, but regulators of RAD51 loading are not well defined. PALB2 is a mediator of BRCA2-RAD51 DNA break localization; it can also bind BRCA1 or form homodimers with DNA-binding activity via its coiled-coil (CC) domain. Here, we created a CC-mutated mouse allele (Palb2CC) that disrupts CC-mediated interactions. While Palb2CC/CC embryos were not viable, remarkably, intercrossing with mice lacking 53BP1, an inhibitor of PALB2-chromatin contacts, produced live births. However, Palb2CC/CC53bp1-/- mice were tumor prone, and cells had limited RAD51 foci. HR remained inefficient because the CC domain was required for PALB2 to bind to single-stranded (ss)DNA overhangs and subsequently promote PALB2 and RAD51 accumulation. These findings underscore the role of ssDNA binding in localizing PALB2 to DNA breaks while establishing genetic interactions that control the post-end resection steps of mammalian HR.

Keywords: 53BP1; BRCA1; BRCA2; DNA end resection; DNA repair; PALB2; RAD51; coiled-coil; double-stranded DNA break; homologous recombination.

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Conflict of interest statement

Declaration of interests All authors declare no competing interests.

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