G6PC3 promotes genome maintenance and is a candidate mammary tumor suppressor

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.

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Publication Details

Journal
JCI Insight
Published
2025-04-22
DOI
https://doi.org/10.1172/jci.insight.186747
Primary Topic
Cancer-related Molecular Pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

G6PC3 promotes genome maintenance and is a candidate mammary tumor suppressor

Þorkell Guðjόnsson, Finn Cilius Nielsen, Ana Moisés da Silva, Judit Börcsök et al.
JCI Insight
Cancer-related Molecular Pathways
article

G6PC3 promotes genome maintenance and is a candidate mammary tumor suppressor

Þorkell Guðjόnsson, Finn Cilius Nielsen, Ana Moisés da Silva, Judit Börcsök, Zoltán Szállási, Asma Tajik, Muthiah Bose, Jayashree Thatte, Morten Frödin, Maria Rossing, Renée X. de Menezes, Jens Vilstrup Johansen, Jos Jonkers, Lumturi Sena, Jan Benada, Xin Li, Ji-Ying Song, Hanneke van der Gulden, Claus Storgaard Sørensen
article en

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.

JCI InsightVol. 10(11)
Semmelweis University (HU), University of Copenhagen (DK), Boston Children's Hospital (US), Rigshospitalet (DK), The Netherlands Cancer Institute (NL), Oncode Institute (NL), Amsterdam Public Health (NL), Danish Cancer Society (DK)
Kræftens Bekæmpelse, European Commission, National Research Foundation, Danmarks Grundforskningsfond, Ministerie van Volksgezondheid, Welzijn en Sport, Lundbeckfonden, China Scholarship Council, Rigshospitalet, Dansk Kræftforsknings Fond, Copenhagen Graduate School for Nanoscience and Nanotechnology, H. Lundbeck A/S, Oncode Institute, School of Medicine, Duke University
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