Hypomorphic Brca2 and Rad51c Double Mutant Mice Display Fanconi Anemia, Cancer and Polygenic Replication Stress

Authors

Karl-Heinz Tomaszowski
Sunetra Roy
Carolina Guerrero
Poojan Shukla
Caezaan Keshvani
Yue Chen
Martina Ott
Xiaogang Wu
Jianhua Zhang
Courtney D DiNardo
Detlev Schindler
Katharina Schlacher

Publication Date

3-11-2023

Journal

Nature Communications

Abstract

The prototypic cancer-predisposition disease Fanconi Anemia (FA) is identified by biallelic mutations in any one of twenty-three FANC genes. Puzzlingly, inactivation of one Fanc gene alone in mice fails to faithfully model the pleiotropic human disease without additional external stress. Here we find that FA patients frequently display FANC co-mutations. Combining exemplary homozygous hypomorphic Brca2/Fancd1 and Rad51c/Fanco mutations in mice phenocopies human FA with bone marrow failure, rapid death by cancer, cellular cancer-drug hypersensitivity and severe replication instability. These grave phenotypes contrast the unremarkable phenotypes seen in mice with single gene-function inactivation, revealing an unexpected synergism between Fanc mutations. Beyond FA, breast cancer-genome analysis confirms that polygenic FANC tumor-mutations correlate with lower survival, expanding our understanding of FANC genes beyond an epistatic FA-pathway. Collectively, the data establish a polygenic replication stress concept as a testable principle, whereby co-occurrence of a distinct second gene mutation amplifies and drives endogenous replication stress, genome instability and disease.

Keywords

Animals, Female, Humans, Mice, BRCA2 Protein, Breast Neoplasms, DNA-Binding Proteins, Fanconi Anemia, Genotype, Mutation, Phenotype

Comments

This article has been corrected. See Nat Commun. 2024 Mar 12;15:2214.

Associated Data

PMID: 36906610