Alternative titles; symbols
HGNC Approved Gene Symbol: GEN1
Cytogenetic location: 2p24.2 Genomic coordinates (GRCh38): 2:17,753,278-17,788,946 (from NCBI)
The human GEN1 gene encodes a 103-kD protein that contains a Rad2/XPG nuclease domain (Ip et al., 2008).
Ishikawa et al. (2004) showed that Drosophila Gen1 had endonuclease and 3-prime-to-5-prime exonuclease activity with both single- and double-stranded DNA substrates in vitro.
Ip et al. (2008) identified nucleases from S. cerevisiae and human cells that promote Holliday junction resolution, in a manner analogous to that shown by the E. coli Holliday junction resolvase RuvC. The human Holliday junction resolvase GEN1 and its yeast ortholog Yen1 were independently identified using 2 distinct experimental approaches: GEN1 was identified by mass spectrometry following extensive fractionation of HeLa cell-free extracts, whereas Yen1 was detected by screening a yeast gene fusion library for nucleases capable of Holliday junction resolution. The eukaryotic Holliday junction resolvases represent a new subclass of the Rad2/XPG family of nucleases. Recombinant GEN1 and Yen1 resolve Holliday junctions by the introduction of symmetrically related cuts across the junction point, to produce nicked duplex products in which the nicks can be readily ligated.
Wechsler et al. (2011) used Bloom syndrome (210900) cells, in which the BLM gene (604610) is inactivated, to analyze human cells compromised for the known Holliday junction dissolution/resolution pathways. Wechsler et al. (2011) showed that depletion of MUS81 (606591) and GEN1, or SLX4 (613278) and GEN1, from Bloom syndrome cells results in severe chromosome abnormalities, such that sister chromatids remain interlinked in a side-by-side arrangement and the chromosomes are elongated and segmented. Wechsler et al. (2011) concluded that normally replicating human cells require Holliday junction processing activities to prevent sister chromatid entanglements and thereby ensure accurate chromosome condensation. This phenotype was not apparent when both MUS81 and SLX4 were depleted from Bloom syndrome cells, suggesting that GEN1 can compensate for their absence. Additionally, Wechsler et al. (2011) showed that depletion of MUS81 or SLX4 reduces the high frequency of sister chromatid exchanges in Bloom syndrome cells, indicating that MUS81 and SLX4 promote sister chromatid exchange formation, in events that may ultimately drive the chromosome instabilities that underpin early-onset cancers associated with Bloom syndrome.
Hartz (2008) mapped the GEN1 gene to chromosome 2p24.2 based on an alignment of the GEN1 sequence (GenBank AK025489) with the genomic sequence (build 36.1).
Hartz, P. A. Personal Communication. Baltimore, Md. 12/3/2008.
Ip, S. C. Y., Rass, U., Blanco, M. G., Flynn, H. R., Skehel, J. M., West, S. C. Identification of Holliday junction resolvases from humans and yeast. Nature 456: 357-361, 2008. [PubMed: 19020614] [Full Text: https://doi.org/10.1038/nature07470]
Ishikawa, G., Kanai, Y., Takata, I., Takeuchi, R., Shimanouchi, K., Ruike, T., Furukawa, T., Kimura, S., Sakaguchi, K. DmGEN, a novel RAD2 family endo-exonuclease from Drosophila melanogaster. Nucleic Acids Res. 32: 6251-6259, 2004. [PubMed: 15576351] [Full Text: https://doi.org/10.1093/nar/gkh962]
Wechsler, T., Newman, S., West, S. C. Aberrant chromosome morphology in human cells defective for Holliday junction resolution. Nature 471: 642-646, 2011. [PubMed: 21399624] [Full Text: https://doi.org/10.1038/nature09790]