DNA damage response pathway (DDR pathway)

DNA damage response pathway Overview

The **DNA damage response pathway** refers collectively to an intricate network of cellular mechanisms responsible for detecting, signaling, and repairing various forms of DNA lesions—including those caused by endogenous metabolic processes or exogenous agents such as chemotherapy. Among these lesions are **DNA crosslinks**, which covalently link nucleotides either within one strand (*intrastrand*) or between strands (*interstrand*)—the latter being particularly cytotoxic because they prevent strand separation required for replication and transcription. Cells employ several major sub-pathways—such as nucleotide excision repair, homologous recombination repair, non-homologous end joining, base excision repair, and mismatch repair—to address different types of DNA damage. Key proteins involved include BRCA1/BRCA2, ATM kinase, CHEK1/CHEK2 kinases among others. Dysfunctional components within these pathways contribute directly to carcinogenesis by allowing accumulation of mutations; conversely these same vulnerabilities are exploited therapeutically using drugs like platinum compounds or PARP inhibitors that induce synthetic lethality in tumor cells with defective DNA repair machinery.[1][2][3][4]

Mechanism of Action

Inhibition of PARP enzymes leads to accumulation of unrepaired single-strand breaks that convert into lethal double-strand breaks during replication.[4] Platinum drugs induce interstrand crosslinks that block replication/transcription and trigger apoptosis if unrepaired.[3][1]

Biological Functions

Safety Considerations

Interacting Drugs

Associated Biomarkers