A Missense Mutation in Rev7 Disrupts Formation of Polζ, Impairing Mouse Development and Repair of Genotoxic Agent-induced DNA Lesions

Abstract

Background: Rev7 encodes a subunit of Pol for translesion DNA synthesis (TLS). Results: We found a Rev7 mutation in mice that causes developmental defects and increases susceptibility for genotoxicity. Conclusion: Rev7 is essential for mouse development through its function in cell proliferation.Significance: These findings demonstrate a unique function of Pol in development that is absent in other TLS polymerases.

Biallelic inactivation of REV7 is associated with Fanconi anemia

“…Together, these data suggest that the Rev7 defect directly alters HPCs, leading to increased lineage engagement, consistent with a DNA damage-mediated mechanism of BMF. nuclei, indicating accumulation of DNA damage (31). The Rev7-deficient mice, therefore, have a very similar defect in development, embryonic lethality, infertility, and DNA damage accumulation, which is also observed in other Fanc -/-mouse models (32).…”

“…-/-and Rev7 C70R mice (30,31). In one model, Rev7 -/-mice exhibited growth retardation and a partial embryonic lethal phenotype, and those mice that survived to adulthood were infertile and showed germ cell aplasia in the testes and ovaries (30).…”

“…In one model, Rev7 -/-mice exhibited growth retardation and a partial embryonic lethal phenotype, and those mice that survived to adulthood were infertile and showed germ cell aplasia in the testes and ovaries (30). In the second model, a missense mutation in Rev7 C70R disrupted Pol ζ assembly, thereby impairing mouse development and the repair of genotoxic agent-induced DNA lesions (31).…”

Roles of mutagenic translesion synthesis in mammalian genome stability, health and disease

“…Thus, Rev7 KO mice are born at sub-Mendelian ratios, are smaller than their littermates and are infertile due a defect in primordial germ cell development that leads to loss of germ cells in ovaries and testes. In addition, Rev7 mutant mice display increased apoptosis in neuroblasts of the embryonic forebrain [23,25].…”

MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection

“…6b-e). However, MAD2L2-L186A and MAD2L2-C70R, respectively defective in REV1 or REV3 interaction 25,26 , were still capable of promoting telomere fusion and telomere-driven genomic instability (Fig. 4b, Extended Data Fig.…”