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

Research output: Contribution to journalArticle

14 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

Fingerprint

Missense Mutation
DNA-Directed DNA Polymerase
Repair
Germ Cells
DNA
M Phase Cell Cycle Checkpoints
Cell proliferation
Cell Proliferation
S Phase
Mutation
DNA Damage
Embryonic Development
Ethylnitrosourea
Cells
Mitomycin
Mutagenesis
Defects
Mammals
Cloning
Infertility

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

A missense mutation in Rev7 disrupts formation of Pol, impairing mouse development and repair of Genotoxic Agent-induced DNA Lesions. / Khalaj, Maryam; Abbasi, Abdolrahim; Yamanishi, Hiroshi; Akiyama, Kouyou; Wakitani, Shuso; Kikuchi, Sotaro; Hirose, Michiko; Yuzuriha, Misako; Magari, Masaki; Degheidy, Heba A.; Abe, Kuniya; Ogura, Atsuo; Hashimoto, Hiroshi; Kunieda, Tetsuo.

In: Journal of Biological Chemistry, Vol. 289, No. 6, 07.02.2014, p. 3811-3824.

Research output: Contribution to journalArticle

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 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, vol. 289, no. 6, pp. 3811-3824. https://doi.org/10.1074/jbc.M113.514752
Khalaj, Maryam ; Abbasi, Abdolrahim ; Yamanishi, Hiroshi ; Akiyama, Kouyou ; Wakitani, Shuso ; Kikuchi, Sotaro ; Hirose, Michiko ; Yuzuriha, Misako ; Magari, Masaki ; Degheidy, Heba A. ; Abe, Kuniya ; Ogura, Atsuo ; Hashimoto, Hiroshi ; Kunieda, Tetsuo. / A missense mutation in Rev7 disrupts formation of Pol, impairing mouse development and repair of Genotoxic Agent-induced DNA Lesions. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 6. pp. 3811-3824.
@article{f9421c0c11fc436dadb358f232f1bacd,
title = "A missense mutation in Rev7 disrupts formation of Pol, 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. 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.",
author = "Maryam Khalaj and Abdolrahim Abbasi and Hiroshi Yamanishi and Kouyou Akiyama and Shuso Wakitani and Sotaro Kikuchi and Michiko Hirose and Misako Yuzuriha and Masaki Magari and Degheidy, {Heba A.} and Kuniya Abe and Atsuo Ogura and Hiroshi Hashimoto and Tetsuo Kunieda",
year = "2014",
month = "2",
day = "7",
doi = "10.1074/jbc.M113.514752",
language = "English",
volume = "289",
pages = "3811--3824",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "6",

}

TY - JOUR

T1 - A missense mutation in Rev7 disrupts formation of Pol, impairing mouse development and repair of Genotoxic Agent-induced DNA Lesions

AU - Khalaj, Maryam

AU - Abbasi, Abdolrahim

AU - Yamanishi, Hiroshi

AU - Akiyama, Kouyou

AU - Wakitani, Shuso

AU - Kikuchi, Sotaro

AU - Hirose, Michiko

AU - Yuzuriha, Misako

AU - Magari, Masaki

AU - Degheidy, Heba A.

AU - Abe, Kuniya

AU - Ogura, Atsuo

AU - Hashimoto, Hiroshi

AU - Kunieda, Tetsuo

PY - 2014/2/7

Y1 - 2014/2/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84893708527&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893708527&partnerID=8YFLogxK

U2 - 10.1074/jbc.M113.514752

DO - 10.1074/jbc.M113.514752

M3 - Article

C2 - 24356953

AN - SCOPUS:84893708527

VL - 289

SP - 3811

EP - 3824

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 6

ER -