Gen1 and Eme1 Play Redundant Roles in DNA Repair and Meiotic Recombination in Mice

Overview

Journal DNA Cell Biol

Publisher Mary Ann Liebert

Specialties Cell Biology
Molecular Biology

Date 2016 Jul 8

PMID 27383418

Citations 10

Authors

Xiaowen Wang

Herui Wang

Bin Guo

Ya Zhang

Yinv Gong

Chi Zhang

Hong Xu

Xiaohui Wu

Affiliations

Soon will be listed here.

Abstract

Resolution of the Holliday junction (HJ) is essential for homologous recombination and DNA repair. In Saccharomyces cerevisiae, HJ resolvase Yen1 and the Mus81-Mms4 complex are redundant in DNA damage repair. In cultured mammalian cells, such redundancy also exists between Yen1 ortholog GEN1 and the Mus81-Mms1 ortholog MUS81-EME1. In this report, we further tested if GEN1 and EME1 redundantly affect HJ-related physiological processes in mice. We found that combined homozygous mutations of Gen1 and Eme1 led to synthetic lethality during early embryonic stages. Homozygous Gen1 mutations did not cause DNA repair deficiency in mouse embryonic fibroblast (MEF) cells, but made heterozygous Eme1 mutant MEFs more sensitive to various DNA-damaging reagents. Gen1 mutations also reduced the meiotic recombination efficiency in Eme1 mutant mice. These results suggest that Gen1 and Eme1 play redundant roles in DNA repair and meiotic recombination in vivo.

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References

Boddy M, Gaillard P, McDonald W, Shanahan P, Yates 3rd J, Russell P . Mus81-Eme1 are essential components of a Holliday junction resolvase. Cell. 2001; 107(4):537-48. DOI: 10.1016/s0092-8674(01)00536-0. View

Chen X, Melchionna R, Denis C, Gaillard P, Blasina A, Van de Weyer I . Human Mus81-associated endonuclease cleaves Holliday junctions in vitro. Mol Cell. 2001; 8(5):1117-27. DOI: 10.1016/s1097-2765(01)00375-6. View

Fricke W, Brill S . Slx1-Slx4 is a second structure-specific endonuclease functionally redundant with Sgs1-Top3. Genes Dev. 2003; 17(14):1768-78. PMC: 196184. DOI: 10.1101/gad.1105203. View

Abraham J, Lemmers B, Hande M, Moynahan M, Chahwan C, Ciccia A . Eme1 is involved in DNA damage processing and maintenance of genomic stability in mammalian cells. EMBO J. 2003; 22(22):6137-47. PMC: 275438. DOI: 10.1093/emboj/cdg580. View

Wu L, Hickson I . The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature. 2003; 426(6968):870-4. DOI: 10.1038/nature02253. View

Ding S, Wu X, Li G, Han M, Zhuang Y, Xu T . Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice. Cell. 2005; 122(3):473-83. DOI: 10.1016/j.cell.2005.07.013. View

Sun L, Jin K, Liu Y, Yang W, Xie X, Ye L . PBmice: an integrated database system of piggyBac (PB) insertional mutations and their characterizations in mice. Nucleic Acids Res. 2007; 36(Database issue):D729-34. PMC: 2238892. DOI: 10.1093/nar/gkm790. View

Holloway J, Booth J, Edelmann W, McGowan C, Cohen P . MUS81 generates a subset of MLH1-MLH3-independent crossovers in mammalian meiosis. PLoS Genet. 2008; 4(9):e1000186. PMC: 2525838. DOI: 10.1371/journal.pgen.1000186. View

Ip S, Rass U, Blanco M, Flynn H, Skehel J, West S . Identification of Holliday junction resolvases from humans and yeast. Nature. 2008; 456(7220):357-61. DOI: 10.1038/nature07470. View

10.

West S . The search for a human Holliday junction resolvase. Biochem Soc Trans. 2009; 37(Pt 3):519-26. PMC: 4120095. DOI: 10.1042/BST0370519. View

11.

Munoz I, Hain K, Declais A, Gardiner M, Toh G, Sanchez-Pulido L . Coordination of structure-specific nucleases by human SLX4/BTBD12 is required for DNA repair. Mol Cell. 2009; 35(1):116-27. DOI: 10.1016/j.molcel.2009.06.020. View

12.

Svendsen J, Smogorzewska A, Sowa M, OConnell B, Gygi S, Elledge S . Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell. 2009; 138(1):63-77. PMC: 2720686. DOI: 10.1016/j.cell.2009.06.030. View

13.

Fekairi S, Scaglione S, Chahwan C, Taylor E, Tissier A, Coulon S . Human SLX4 is a Holliday junction resolvase subunit that binds multiple DNA repair/recombination endonucleases. Cell. 2009; 138(1):78-89. PMC: 2861413. DOI: 10.1016/j.cell.2009.06.029. View

14.

Lorenz A, West S, Whitby M . The human Holliday junction resolvase GEN1 rescues the meiotic phenotype of a Schizosaccharomyces pombe mus81 mutant. Nucleic Acids Res. 2009; 38(6):1866-73. PMC: 2847240. DOI: 10.1093/nar/gkp1179. View

15.

Blanco M, Matos J, Rass U, Ip S, West S . Functional overlap between the structure-specific nucleases Yen1 and Mus81-Mms4 for DNA-damage repair in S. cerevisiae. DNA Repair (Amst). 2010; 9(4):394-402. DOI: 10.1016/j.dnarep.2009.12.017. View

16.

Tay Y, Wu L . Overlapping roles for Yen1 and Mus81 in cellular Holliday junction processing. J Biol Chem. 2010; 285(15):11427-32. PMC: 2857021. DOI: 10.1074/jbc.M110.108399. View

17.

Rass U, Compton S, Matos J, Singleton M, Ip S, Blanco M . Mechanism of Holliday junction resolution by the human GEN1 protein. Genes Dev. 2010; 24(14):1559-69. PMC: 2904945. DOI: 10.1101/gad.585310. View

18.

Petermann E, Helleday T . Pathways of mammalian replication fork restart. Nat Rev Mol Cell Biol. 2010; 11(10):683-7. DOI: 10.1038/nrm2974. View

19.

Cejka P, Plank J, Bachrati C, Hickson I, Kowalczykowski S . Rmi1 stimulates decatenation of double Holliday junctions during dissolution by Sgs1-Top3. Nat Struct Mol Biol. 2010; 17(11):1377-82. PMC: 2988882. DOI: 10.1038/nsmb.1919. View

20.

Ho C, Mazon G, Lam A, Symington L . Mus81 and Yen1 promote reciprocal exchange during mitotic recombination to maintain genome integrity in budding yeast. Mol Cell. 2010; 40(6):988-1000. PMC: 3021384. DOI: 10.1016/j.molcel.2010.11.016. View