A Population-Specific PARP1 Gene Variation Modulates PARP Trapping.

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Poly-(ADP-ribose) polymerase inhibitors (PARPi) are crucial in cancer therapy, particularly for homologous recombination-deficient (HRD) cancers.
• PARPi function by inhibiting PARP1, but their efficacy varies due to differences in PARP1 retention on damaged DNA.
• Allosteric activation of PARP1, involving helical domain destabilization, is key for chromatin retention and synthetic lethality.

Purpose of the Study:

• To investigate the impact of a common human polymorphism in the PARP1 helical domain (HD) on the efficacy of the clinical PARPi talazoparib.
• To elucidate the mechanistic differences in talazoparib's interaction with different PARP1 variants.

Main Methods:

• Utilized a common human polymorphism within the PARP1 HD.
• Analyzed talazoparib's effect on PARP1 retention, XRCC1 recruitment, and cell killing in cancer models.
• Characterized talazoparib's behavior as Type-I or Type-II PARPi based on PARP1 genotype.

Main Results:

• A specific PARP1 variant (PARP1^V762) significantly enhanced talazoparib-induced allosteric retention on chromatin.
• This enhanced retention led to prolonged XRCC1 recruitment and increased cancer cell killing compared to the wild-type PARP1^A762.
• Talazoparib exhibited a switch from Type-II to a pro-retention Type-I behavior in the presence of the PARP1^V762 variant.

Conclusions:

• PARPi efficacy and tolerability are influenced by the patient's specific PARP1 allele.
• This highlights the potential for variant-guided cancer therapies to optimize treatment outcomes.
• Understanding PARP1 polymorphisms is essential for developing more effective and safer PARPi-based treatments.