Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress

Karl-Heinz Tomaszowski, Sunetra Roy, Carolina Guerrero, Poojan Shukla, Caezaan Keshvani, Yue Chen, Martina Ott, Xiaogang Wu, Jianhua Zhang, Courtney D. DiNardo, Detlev Schindler and Katharina Schlacher ()
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Karl-Heinz Tomaszowski: The University of Texas MD Anderson Cancer Center
Sunetra Roy: The University of Texas MD Anderson Cancer Center
Carolina Guerrero: The University of Texas MD Anderson Cancer Center
Poojan Shukla: The University of Texas MD Anderson Cancer Center
Caezaan Keshvani: The University of Texas MD Anderson Cancer Center
Yue Chen: The University of Texas MD Anderson Cancer Center
Martina Ott: The University of Texas MD Anderson Cancer Center
Xiaogang Wu: The University of Texas MD Anderson Cancer Center
Jianhua Zhang: The University of Texas MD Anderson Cancer Center
Courtney D. DiNardo: The University of Texas MD Anderson Cancer Center
Detlev Schindler: University of Wuerzburg
Katharina Schlacher: The University of Texas MD Anderson Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36933-y

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