Researchers from RepliFate have uncovered a novel DNA repair pathway orchestrated by the enzyme PARP1 that targets toxic DNA-protein crosslinks (DPCs). The study, published in Nature Communications, provides new insights into how cells handle these dangerous lesions and may explain the synergistic effects of certain cancer treatments.
Key findings:
- PARP1 senses DPCs on single-stranded DNA gaps and those flanked by DNA nicks, like topoisomerase 1 cleavage complexes (TOP1ccs)
- PARP1 directly modifies the crosslinked proteins with poly(ADP-ribose) chains
- This PARylation triggers ubiquitination and subsequent degradation of the DPCs by the proteasome and other proteases
- Without PARP1-mediated repair, TOP1cc-like lesions persist and cause replication fork disassembly when encountered during DNA replication
The researchers used innovative biochemical approaches in Xenopus egg extracts and human cells to elucidate this pathway. Their findings suggest PARP1 is a primary sensor for certain types of DPCs, especially those caused by TOP1 poisons used in chemotherapy.
This work provides a mechanistic explanation for why PARP inhibitors synergize with TOP1 poisons in killing cancer cells – a combination currently being explored in clinical trials. By preventing PARP1-mediated DPC repair, more lesions persist to disrupt replication, leading to increased DNA damage and cell death.
The study opens new avenues for understanding fundamental DNA repair processes and developing more effective cancer treatments targeting DNA repair pathways.
Figure Mechanism of PARP1-mediated DPC resolution.
