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J Biol Chem 2014 Feb 7;289(6):3811-24

A missense mutation in Rev7 disrupts formation of Pol¿, impairing mouse development and repair of genotoxic agent-induced DNA lesions.

Khalaj M, Abbasi A, Yamanishi H, Akiyama K, Wakitani S, Kikuchi S, Hirose M, Yuzuriha M, Magari M, Degheidy HA, Abe K, Ogura A, Hashimoto H, Kunieda T


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 ¿ (Pol¿), 1 of 10 translesion DNA synthesis polymerases known in mammals. The mutant REV7 did not interact with REV3, the catalytic subunit of Pol¿. Rev7(C70R/C70R) cells showed decreased proliferation, increased apoptosis, and arrest in S phase with extensive ¿H2AX 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 Pol¿ preserving DNA integrity during cell proliferation, which is required in highly proliferating embryonic cells.

Category: Journal Article
PubMed ID: #24356953 DOI: 10.1074/jbc.M113.514752
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2014-03-04 Entry Last Modified: 2014-04-14