Homology-directed repair deficiency (HRd) encompasses mutations in multiple genes yet is treated clinically as a single entity. Here, through parallel analyses of isogenic knockouts of multiple HR pathway genes, integrating multi-omic analyses with genome-wide CRISPR-Cas9-dependency and resistance screens, we show that HRd is not a single entity but exists along a molecular and functional continuum. BRCA1, BRCA2, PALB2, RAD51C, and RAD51D mutants shared many HRd-associated mutational signatures, while RAD51B, BRIP1, CDK12 exhibited distinct genomic patterns. Functional heterogeneity was equally apparent: synthetic lethal interactions including CIP2A and a novel dependency on PRDX1 were penetrant across most HRd genotypes, whereas FANCM dependency was linked to HRd subtypes characterized by tandem duplications. PARPi resistance screens in distinct HRd contexts uncovered BRIP1 and RECQL5 as new BRCA2-specific resistance genes. HRd is thus a complex continuum, underscoring why modernizing the molecular taxonomy utilizing all genomic features available per patient is crucial to informing precision interventions.
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