PARP1 revisited - integrating DNA repair, replication and therapeutics.

PARP1 recognizes diverse DNA and chromatin structures—such as unligated Okazaki fragments, reversed forks, G-quadruplexes, and R-loops—by interpreting lesion geometry, topology, and chromatin context.

• Why it matters: PARP1’s substrate recognition and whether different DNA structures produce distinct ADP-ribosylation outputs are unclear, limiting mechanistic understanding of genome maintenance and therapy response.
• What they did: This Review integrates evidence that PARP1 acts as a non-uniform sensor, dynamically regulating chromatin accessibility, repair-factor recruitment, replication fork remodeling, transcription-replication conflicts, and PARP1 turnover.
• The result: PARP inhibitor efficacy, toxicity, and resistance are linked to combined effects of PARP1 retention, replication stress, repair-pathway choice, chromatin remodeling, and tumor context—not only catalytic inhibition or BRCA1/BRCA2 status.

AI summary of the abstract · may contain errors · not medical advice · read the paper.