DNA damage response signaling pathway (DDR)

The DNA damage response (DDR) signaling pathway is a sophisticated network of cellular processes that detect and repair DNA lesions to maintain genomic stability (Jackson & Bartek, Nature, 2009). It comprises sensors (e.g., MRN complex), transducers (e.g., ATM, ATR, and DNA-PK kinases), and effectors (e.g., CHK1, CHK2, and p53) that coordinate cell cycle arrest and repair or trigger apoptosis if damage is irreparable (O'Connor, Molecular Cell, 2015). In oncology, the DDR is a critical therapeutic target because many tumors harbor defects in specific repair pathways, such as BRCA1/2 mutations, making them reliant on alternative DDR mechanisms (Lord & Ashworth, Nature, 2012). This vulnerability is exploited through synthetic lethality, most notably with PARP inhibitors, which selectively kill HR-deficient cancer cells (Pearl et al., Nature Reviews Cancer, 2015). Beyond PARP, inhibitors of ATR, ATM, and WEE1 are currently in clinical development to enhance the efficacy of chemotherapy and radiotherapy or to overcome resistance (Pilié et al., Nature Reviews Clinical Oncology, 2019).

Other names

DNA damage responseDDRDNA repair signalingGenomic integrity maintenance system

Inhibition of DNA repair enzymes and checkpoint kinases to induce synthetic lethality or sensitize cells to DNA-damaging agents.