Mechanisms and regulation of proteolytic DNA-protein crosslink repair.

Proteolytic repair of DNA-protein crosslinks relies on ubiquitylation to license proteasome or SPRTN-mediated proteolysis, enabling removal of bulky enzyme-DNA and crosslink-agent lesions.

• Why it matters: DNA-protein crosslinks block replication and transcription, so dedicated repair is needed to maintain genome stability and cellular homeostasis.
• What they did: This Review synthesizes how proteolytic DPC repair operates across replication-coupled, transcription-coupled, and global genome pathways, converging on ubiquitylation of the crosslinked protein.
• The result: Defective DPC proteolysis is linked to genome instability, premature ageing, and cancer predisposition, highlighting the pathway’s importance for long-term cellular integrity.

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