title: A missense mutation in Rev7 disrupts formation of Polζ, impairing mouse development and repair of genotoxic agent-induced DNA lesions.
abstract: Repro22 is a mutant mouse produced via N-ethyl-N-nitrosourea-induced mutagenesis that shows sterility with germ cell depletion caused by defective proliferation of primordial germ cells, decreased body weight, and partial lethality during embryonic development. Using a positional cloning strategy, we identified a missense mutation in Rev7/Mad2l2 (Rev7(C70R)) and confirmed that the mutation is the cause of the defects in repro22 mice through transgenic rescue with normal Rev7. Rev7/Mad2l2 encodes a subunit of DNA polymerase ζ (Polζ), 1 of 10 translesion DNA synthesis polymerases known in mammals. The mutant REV7 did not interact with REV3, the catalytic subunit of Polζ. Rev7(C70R/C70R) cells showed decreased proliferation, increased apoptosis, and arrest in S phase with extensive γH2AX foci in nuclei that indicated accumulation of DNA damage after treatment with the genotoxic agent mitomycin C. The Rev7(C70R) mutation does not affect the mitotic spindle assembly checkpoint. These results demonstrated that Rev7 is essential in resolving the replication stalls caused by DNA damage during S phase. We concluded that Rev7 is required for primordial germ cell proliferation and embryonic viability and development through the translesion DNA synthesis activity of Polζ preserving DNA integrity during cell proliferation, which is required in highly proliferating embryonic cells.
authors.affiliation: From the Graduate School of Natural Science and Technology and.
authors.forename: Maryam
authors.initials: M
authors.lastname: Khalaj
authors.forename: Abdolrahim
authors.initials: A
authors.lastname: Abbasi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamanishi
authors.forename: Kouyou
authors.initials: K
authors.lastname: Akiyama
authors.forename: Shuso
authors.initials: S
authors.lastname: Wakitani
authors.forename: Sotaro
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Michiko
authors.initials: M
authors.lastname: Hirose
authors.forename: Misako
authors.initials: M
authors.lastname: Yuzuriha
authors.forename: Masaki
authors.initials: M
authors.lastname: Magari
authors.forename: Heba A
authors.initials: HA
authors.lastname: Degheidy
authors.forename: Kuniya
authors.initials: K
authors.lastname: Abe
authors.forename: Atsuo
authors.initials: A
authors.lastname: Ogura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hashimoto
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kunieda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004257:DNA Polymerase II / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D005260:Female; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism; D064246:Mad2 Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D016685:Mitomycin / Q000494:pharmacology*; D020125:Mutation, Missense; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D000075223:Poly-ADP-Ribose Binding Proteins; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism
chemical_list: D004257:DNA Polymerase II; D004259:DNA-Directed DNA Polymerase; D064246:Mad2 Proteins; D016685:Mitomycin; D019384:Nucleic Acid Synthesis Inhibitors; D000075223:Poly-ADP-Ribose Binding Proteins; C577699:Mad2l2 protein, mouse; C486862:REV3L protein, mouse; C485610:Pole protein, mouse
keywords: Cell Proliferation; DNA Polymerase; Embryo; Mouse Genetics; Mutant