FANCM promotes PARP inhibitor resistance by minimizing ssDNA gap formation and counteracting resection inhibition

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• Poly(ADP-ribose) polymerase inhibitors (PARPis) are effective cancer treatments for tumors with homologous recombination (HR) gene mutations.
• The precise mechanisms governing PARPi-induced lethality, particularly the roles of DNA repair proteins beyond the core Fanconi anemia (FA) complex, are not fully understood.

Purpose of the Study:

• To investigate the role of FANCM in cellular response to PARPi treatment.
• To elucidate the mechanisms by which FANCM influences PARPi resistance and DNA damage accumulation.

Main Methods:

• CRISPR-Cas9 mediated depletion of FANCM in cancer cell lines.
• Assessment of homologous recombination (HR) proficiency, DNA damage markers (e.g., ssDNA gaps, collapsed forks), and cell death.
• Analysis of the involvement of 53BP1 and PRIMPOL in PARPi resistance.

Main Results:

• FANCM depletion confers sensitivity to PARPis independently of the core FA complex and BRCA1.
• FANCM-depleted cells show increased DNA damage in the second S phase post-PARPi, due to elevated single-strand DNA (ssDNA) gap formation.
• Reduced resection of collapsed forks in FANCM-depleted cells, which is rescued by 53BP1 deletion, mitigating PARPi sensitivity.
• FANCM depletion leads to increased chromatin bridges and micronuclei formation, contributing to cell death.

Conclusions:

• FANCM plays a critical role in promoting resistance to PARPis by counteracting 53BP1-mediated DNA damage accumulation.
• FANCM acts independently of the core FA complex in regulating PARPi sensitivity.
• Understanding FANCM's function offers potential new therapeutic strategies for enhancing PARPi efficacy in cancer treatment.