Homology-directed DNA repair pathway (HDR) (HDR)

The homology-directed DNA repair (HDR) pathway is a high-fidelity mechanism responsible for repairing double-strand breaks (DSBs) in DNA by using a homologous template, typically a sister chromatid, which restricts its activity to the S and G2 phases of the cell cycle [5, 11]. This complex pathway involves a coordinated series of events including DNA end resection, homology search, and strand invasion, mediated by key proteins such as the MRN complex, ATM/ATR kinases, BRCA1, BRCA2, PALB2, and the RAD51 recombinase [6, 10]. Deficiencies in these components, collectively known as Homologous Recombination Deficiency (HRD), result in genomic instability and are a primary driver of hereditary and sporadic cancers, including breast, ovarian, and prostate malignancies [4, 9]. Therapeutically, the HDR pathway is exploited through synthetic lethality, most notably with PARP inhibitors that selectively target HRD-positive cells, and through the development of inhibitors against ATR, ATM, and CHK1 to overcome resistance or enhance the efficacy of DNA-damaging therapies [2, 13]. Understanding the status of this pathway via biomarkers like BRCA mutations or HRD scores is critical for patient stratification and the successful application of these targeted treatments [14, 16]. Additionally, the HDR pathway is harnessed in precision gene editing technologies, such as CRISPR-Cas9, to facilitate accurate gene knock-ins and corrections by providing exogenous donor templates [10, 17].

Other names

Homology-directed DNA repair pathway componentsHomologous recombination repair pathwayHRR pathwayHDR pathwayHomologous recombinationHR pathwayHomology-directed repair

Synthetic lethality via PARP inhibition; inhibition of DNA damage signaling and repair; potentiation of genotoxic therapies.