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Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress
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Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress
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Journal Article
Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress
2023
Overview
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.
Tomaszowski et al show that co-mutations in Brca2 and Rad51c synergistically drive cancer and developmental disease, which was unexpected given their epistatic DNA repair roles, and expands our understanding of their tumor suppressive functions.
