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

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 post-end resection steps in mammalian HR.

ORGANISM(S): Mus musculus

PROVIDER: GSE299657 | GEO | 2025/07/23

REPOSITORIES: GEO

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

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