Apoptosis pathway induction via transcription blockage by crosslinked DNA lesions

Crosslinked DNA lesions, such as DNA–protein crosslinks or interstrand crosslinks, are highly cytotoxic because they block essential DNA transactions including transcription and replication. When transcription machinery (especially RNA polymerase II) encounters these lesions, it stalls, triggering the recruitment of specialized repair pathways—particularly transcription-coupled nucleotide excision repair (TC-NER), involving proteins such as CSB (ERCC6) and CSA (ERCC8). Persistent blockage or failed repair results in the activation of checkpoint kinases (ATM/ATR), stabilization of p53, and induction of an apoptotic program to eliminate the damaged cell. This process is fundamental to the cytotoxic action of many chemotherapeutic agents (e.g., cisplatin), but also underlies tissue degeneration in genetic diseases of DNA repair deficiency (e.g., Cockayne syndrome). This process is not a singular, druggable molecular target but rather a critical pathway integrating DNA damage recognition, damage signaling, and programmed cell death relevant to both drug development and disease etiology.

Other names

Transcriptional apoptosis induction by DNA crosslinksDNA crosslink-induced apoptotic signaling

Formation of DNA crosslinks blocks transcription elongation, leading to stalling of RNA polymerase II. Persistent transcription blockage triggers recruitment of repair factors (e.g., Cockayne syndrome proteins CSB/CSA). Failure to resolve the block or excessive damage leads to activation of checkpoint signaling (often via p53, ATM/ATR pathways) and ultimately to induction of apoptosis.