A missense mutation in Rev7 disrupts formation of Pol, impairing mouse development and repair of Genotoxic Agent-induced DNA Lesions

Maryam Khalaj, Abdolrahim Abbasi, Hiroshi Yamanishi, Kouyou Akiyama, Shuso Wakitani, Sotaro Kikuchi, Michiko Hirose, Misako Yuzuriha, Masaki Magari, Heba A. Degheidy, Kuniya Abe, Atsuo Ogura, Hiroshi Hashimoto, Tetsuo Kunieda

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15 Citations (Scopus)

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. 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 (Rev7C70R) 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 (Pol), 1 of 10 translesion DNA synthesis polymerases known in mammals. The mutant REV7 did not interact with REV3, the catalytic subunit of Pol. Rev7C70R/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 Rev7C70R 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 Pol preserving DNA integrity during cell proliferation, which is required in highly proliferating embryonic cells.

Original languageEnglish
Pages (from-to)3811-3824
Number of pages14
JournalJournal of Biological Chemistry
Volume289
Issue number6
DOIs
Publication statusPublished - Feb 7 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Khalaj, M., Abbasi, A., Yamanishi, H., Akiyama, K., Wakitani, S., Kikuchi, S., Hirose, M., Yuzuriha, M., Magari, M., Degheidy, H. A., Abe, K., Ogura, A., Hashimoto, H., & Kunieda, T. (2014). A missense mutation in Rev7 disrupts formation of Pol, impairing mouse development and repair of Genotoxic Agent-induced DNA Lesions. Journal of Biological Chemistry, 289(6), 3811-3824. https://doi.org/10.1074/jbc.M113.514752