FANCA Deficiency Induces Oncogenic R-Loop Dependent Synthetic Lethality with PARP1 Inhibitors

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• Synthetic lethality (SL) is key to PARP1 inhibitor (PARPi) efficacy in homologous recombination (HR) deficient cancers.
• Expanding SL to other DNA damage response (DDR) deficiencies remains a challenge.

Purpose of the Study:

• To identify novel DDR gene mutations conferring PARPi sensitivity using in vivo CRISPR screening.
• To explore the mechanism of FANCA deficiency in driving PARPi synthetic lethality.

Main Methods:

• In vivo CRISPR screening to identify DDR genes impacting tumorigenesis and PARPi sensitivity.
• Validation of FANCA deficiency in diverse human cancer models.
• Investigating the molecular mechanisms of FANCA's role in DNA repair and PARPi response.

Main Results:

• FANCA deficiency was identified as a driver of PARPi synthetic lethality.
• FANCA deficiency disrupts Okazaki fragment maturation (OFM), leading to DNA gaps and RPA exhaustion under PARPi treatment.
• This function requires FANCA's interaction with FEN1, independent of its role in interstrand crosslink repair.

Conclusions:

• FANCA plays a novel, non-canonical role in FEN1-mediated OFM, particularly at R loops during PARPi treatment.
• This mechanism provides a new avenue for leveraging PARPi synthetic lethality in FANCA-mutant cancers.