Homologous recombination DNA repair machinery (HRR)

The homologous recombination DNA repair machinery is a high-fidelity biological system responsible for repairing complex DNA damage, specifically double-strand breaks (DSBs) and interstrand crosslinks (Li & Heyer, 2008). This machinery operates predominantly during the S and G2 phases of the cell cycle, utilizing a homologous DNA template—usually a sister chromatid—to ensure the accurate restoration of the genetic code (Prakash et al., 2015). Central to this process are proteins such as BRCA1, BRCA2, RAD51, and the MRN complex, which work in a coordinated fashion to identify breaks, resect DNA ends, and facilitate strand invasion (Krejci et al., 2012). Deficiencies in this pathway, collectively termed homologous recombination deficiency (HRD), lead to significant genomic instability and are strongly associated with an increased risk of breast, ovarian, prostate, and pancreatic cancers (Lord & Ashworth, 2016). In oncology, this machinery is a critical therapeutic target; PARP inhibitors exploit the HRD phenotype through synthetic lethality, selectively inducing cell death in tumor cells while sparing normal tissue (Farmer et al., 2005). Beyond PARP inhibition, novel strategies are targeting other components like RAD51 and Pol theta to overcome drug resistance and expand the utility of DNA-repair-targeted therapies (Trendel et al., 2019).

Other names

Homologous recombination repair pathwayHR pathwayDouble-strand break repair by homologous recombination

The primary therapeutic strategy involves synthetic lethality, where PARP inhibitors block the repair of single-strand breaks, leading to double-strand breaks that HR-deficient cells cannot repair, resulting in apoptosis (Lord & Ashworth, 2017). Direct inhibition of HR components like RAD51 is also being explored to sensitize tumors to DNA-damaging therapies (Trendel et al., 2019).