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

## TL;DR

This study shows that FANCA deficiency causes cancer cell death when combined with PARP1 inhibitors, offering a new treatment strategy for certain cancers.

## Contribution

The paper reveals a new, non-canonical role for FANCA in DNA repair that enables synthetic lethality with PARP1 inhibitors.

## Key findings

- FANCA deficiency causes PARP1 inhibitor sensitivity through disrupted Okazaki fragment maturation.
- FANCA interacts with FEN1 to repair R loops during PARP1 inhibition, independent of its role in crosslink repair.
- FANCA-mutant cancers may benefit from PARP1 inhibitor therapy based on this synthetic lethal mechanism.

## Abstract

Synthetic lethality (SL) underlies the success of PARP1 inhibitors (PARPi) in treating homologous recombination (HR) deficient cancers, but extending this paradigm to other DNA damage response (DDR) deficiencies has proven challenging. We performed an in vivo CRISPR screen to identify DDR gene mutations that both enhance tumorigenesis and confer sensitivity to PARPi. Our screen identified FANCA deficiency as a driver of PARPi SL that was validated across diverse human cancer models. FANCA deficiency does not impair HR but disrupts Okazaki fragment maturation (OFM), causing lagging strand gaps and RPA exhaustion upon PARPi treatment. These effects require FANCA interaction with FEN1, independently of its canonical role in interstrand crosslink repair. We find FANCA-mediated FEN1 recruitment is required for OFM at oncogene-associated R loops during PARPi treatment. These findings establish a novel and non-canonical function for FANCA in FEN1-mediated OFM that can be leveraged for PARPi synthetic lethality in FANCA-mutant cancers.