GEN1, Holliday junction 5' flap endonuclease explained

GEN1, Holliday junction 5' flap endonuclease is a protein that in humans is encoded by the GEN1 gene.^[1]

Function

This gene encodes a member of the Rad2/xeroderma pigmentosum group G nuclease family, whose members are characterized by N-terminal and internal xeroderma pigmentosum group G nuclease domains followed by helix-hairpin-helix domains and disordered C-terminal domains. The protein encoded by this gene is involved in resolution of Holliday junctions, which are intermediate four-way structures that covalently link DNA during homologous recombination and double-strand break repair. The protein resolves Holliday junctions by creating dual incisions across the junction to produce nicked duplex products that can be ligated. In addition, this protein has been found to localize to centrosomes where it has been implicated in regulation of centrosome integrity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016].

Redundancy with EME1/MUS81

The GEN1 endonuclease shares redundancy with the EME1/MUS81 protein complex for DNA damage repair in mammalian cells.^[2] GEN1 and EME1/MUS81, in mice, have redundant functions with respect to their contributions to Holliday junction processing. When mice had homozygous mutations for both Gen1 and Eme1, they exhibited synthetic lethality at an early embryonic stage.^[2] Gen1 mutant homozygosity, alone, in mice did not cause a DNA repair deficiency. However, if mice homozygous for mutant Gen1 were also heterozyous for an Emc1 mutation, they displayed elevated sensitivity to DNA damaging agents. These observations indicated that GEN1 and EME1 have redundant roles in DNA repair. Gen1 and Emc1 also appear to have redundant roles in meiotic recombination.^[2]

Further reading

• Ip SC, Rass U, Blanco MG, Flynn HR, Skehel JM, West SC . Identification of Holliday junction resolvases from humans and yeast . Nature . 456 . 7220 . 357–61 . 2008 . 19020614 . 10.1038/nature07470 . 2008Natur.456..357I . 4362699 .
• Lorenz A, West SC, Whitby MC . The human Holliday junction resolvase GEN1 rescues the meiotic phenotype of a Schizosaccharomyces pombe mus81 mutant . Nucleic Acids Res. . 38 . 6 . 1866–73 . 2010 . 20040574 . 2847240 . 10.1093/nar/gkp1179 .
• Rose JE, Behm FM, Drgon T, Johnson C, Uhl GR . Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score . Mol. Med. . 16 . 7–8 . 247–53 . 2010 . 20379614 . 2896464 . 10.2119/molmed.2009.00159 .
• Turnbull C, Hines S, Renwick A, Hughes D, Pernet D, Elliott A, Seal S, Warren-Perry M, Gareth Evans D, Eccles D, Stratton MR, Rahman N . Mutation and association analysis of GEN1 in breast cancer susceptibility . Breast Cancer Res. Treat. . 124 . 1 . 283–8 . 2010 . 20512659 . 3632835 . 10.1007/s10549-010-0949-1 .
• Turnbull C, Hines S, Renwick A, Hughes D, Pernet D, Elliott A, Seal S, Warren-Perry M, Gareth Evans D, Eccles D, Stratton MR, Rahman N . Mutation and association analysis of GEN1 in breast cancer susceptibility . Breast Cancer Res. Treat. . 124 . 1 . 283–8 . 2010 . 20512659 . 3632835 . 10.1007/s10549-010-0949-1 .
• Liu Y, Shete S, Wang LE, El-Zein R, Etzel CJ, Liang FW, Armstrong G, Tsavachidis S, Gilbert MR, Aldape KD, Xing J, Wu X, Wei Q, Bondy ML . Gamma-radiation sensitivity and polymorphisms in RAD51L1 modulate glioma risk . Carcinogenesis . 31 . 10 . 1762–9 . 2010 . 20610542 . 2981459 . 10.1093/carcin/bgq141 .
• Rass U, Compton SA, Matos J, Singleton MR, Ip SC, Blanco MG, Griffith JD, West SC . Mechanism of Holliday junction resolution by the human GEN1 protein . Genes Dev. . 24 . 14 . 1559–69 . 2010 . 20634321 . 2904945 . 10.1101/gad.585310 .
• Flachsbart F, Franke A, Kleindorp R, Caliebe A, Blanché H, Schreiber S, Nebel A . Investigation of genetic susceptibility factors for human longevity - a targeted nonsynonymous SNP study . Mutat. Res. . 694 . 1–2 . 13–9 . 2010 . 20800603 . 10.1016/j.mrfmmm.2010.08.006 .
• Rodrigue A, Coulombe Y, Jacquet K, Gagné JP, Roques C, Gobeil S, Poirier G, Masson JY . The RAD51 paralogs ensure cellular protection against mitotic defects and aneuploidy . J. Cell Sci. . 126 . Pt 1 . 348–59 . 2013 . 23108668 . 10.1242/jcs.114595 . free .

Notes and References

1. Web site: Entrez Gene: GEN1, Holliday junction 5' flap endonuclease. 2017-10-16.
2. Wang X, Wang H, Guo B, Zhang Y, Gong Y, Zhang C, Xu H, Wu X . 6 . Gen1 and Eme1 Play Redundant Roles in DNA Repair and Meiotic Recombination in Mice . DNA and Cell Biology . 35 . 10 . 585–590 . October 2016 . 27383418 . 6445196 . 10.1089/dna.2015.3022 .