# G6PC3 promotes genome maintenance and is a candidate mammary tumor suppressor

## TL;DR

This study identifies G6PC3 as a potential tumor suppressor in breast cancer by showing its role in maintaining genome integrity.

## Contribution

The study introduces G6PC3 as a novel candidate mammary tumor suppressor based on functional and genetic analyses.

## Key findings

- G6PC3-deficient cells show increased DNA damage markers and impaired homologous recombination repair.
- G6PC3 promotes the expression of homologous recombination repair genes like BRCA1.
- G6PC3 deficiency accelerates mammary tumor formation in mice with Trp53 loss.

## Abstract

Mutations in genome maintenance factors drive sporadic and hereditary breast cancers. Here, we searched for potential drivers based on germline DNA analysis from a cohort consisting of patients with early-onset breast cancer negative for BRCA1/BRCA2 mutations. This revealed candidate genes that subsequently were subjected to RNA interference–based (RNAi-based) phenotype screens to reveal genome integrity effects. We identified several genes with functional roles in genome maintenance, including Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3), SMC4, and CCDC108. Notably, G6PC3-deficient cells exhibited increased levels of γH2AX and micronuclei formation, along with defects in homologous recombination (HR) repair. Consistent with these observations, G6PC3 was required for the efficient recruitment of BRCA1 to sites of DNA double-strand breaks (DSBs). RNA-Seq analysis revealed that G6PC3 promotes the expression of multiple homologous recombination repair genes, including BRCA1. Through CRISPR-Select functional-genetic phenotype analysis of G6PC3 germline mutations, we identified 2 germline G6PC3 variants displaying partial loss of function. Furthermore, our study demonstrated that G6pc3 deficiency accelerates mammary tumor formation induced by Trp53 loss in mice. In conclusion, our cohort-based functional analysis has unveiled genome maintenance factors and identified G6PC3 as a potential candidate tumor suppressor in breast cancer.

This study identifies putative tumor suppressors supporting genome maintenance, with a functional focus on G6PC3.