DNA damage response pathways and apoptosis regulators (DDR/Apoptosis regulators)

The DNA damage response (DDR) pathways and apoptosis regulators comprise a complex network of signaling cascades and proteins dedicated to maintaining genomic integrity and deciding cell fate (Jackson & Bartek, 2009, Nature). DDR pathways detect DNA lesions, signal their presence, and coordinate repair through mechanisms like base excision repair (BER), homologous recombination (HR), and non-homologous end joining (NHEJ) (Lord & Ashworth, 2012, Nature Reviews Cancer). Key sensors and transducers include ATM, ATR, and PARP, which monitor for double-strand and single-strand breaks (O'Connor, 2015, Molecular Cell). If damage is irreparable, these pathways interface with apoptosis regulators—such as the Bcl-2 family and p53—to trigger programmed cell death, preventing the propagation of oncogenic mutations (Aubrey et al., 2018, Cell Death & Differentiation). In oncology, these pathways are frequently exploited; for instance, PARP inhibitors utilize synthetic lethality in BRCA-deficient cells, while Bcl-2 inhibitors like venetoclax directly induce apoptosis in hematologic malignancies (Czabotar et al., 2014, Nature Reviews Molecular Cell Biology). Therapeutic targeting of these systems aims to overcome chemoresistance and selectively kill cancer cells with pre-existing repair defects.

Other names

DDR machineryDNA repair and cell death pathwaysGenomic integrity networkProgrammed cell death regulators

Inhibition of DNA repair enzymes (e.g., PARP, ATR, ATM) to induce synthetic lethality or sensitize cells to DNA-damaging agents; antagonism of anti-apoptotic proteins (e.g., Bcl-2, Mcl-1) to directly trigger programmed cell death.