Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: CCNB1IP1
Cytogenetic location: 14q11.2 Genomic coordinates (GRCh38) : 14:20,311,370-20,333,279 (from NCBI)
HEI10 is a member of the E3 ubiquitin ligase family and functions in progression of the cell cycle through G(2)/M.
By screening a HeLa cell cDNA library for enhancement of invasive filamentous growth of yeast, Toby et al. (2003) identified a partial cDNA for HEI10 (human enhancer of invasion-10). By database mining, they assembled a full-length cDNA, which encodes a deduced 277-amino acid protein with a predicted molecular mass of 32 kD. The protein contains a divergent RING finger motif in the N terminus, a coiled-coil domain, and cyclin and cyclin-dependent kinase phosphorylation sites in the C terminus. Northern blot analysis identified a 1.6-kb HEI10 transcript that was expressed at high levels in heart, moderate levels in kidney and liver, and low levels in placenta, brain, and lung. Toby et al. (2003) noted that the 87% sequence identity shared by the human and mouse HEI10 orthologs is slightly higher than the average identified by Makalowski et al. (1996).
Using yeast 2-hybrid analysis, Toby et al. (2003) demonstrated the interaction of HEI10 with cyclin B1 (123836) and the E2 ubiquitin-conjugating enzyme UbcH7 (603721). Deletion constructs showed that the RING finger domain is required for induction of filamentous growth. Immunofluorescence analysis of human cell lines using an HEI10 antibody showed nuclear localization of HEI10, with strong expression during cellular growth and chromosomal association during mitosis. HEI10 expression in Xenopus oocytes showed that HEI10 acts as an E3 ubiquitin ligase, causing delayed entry into mitosis by reducing cyclin B levels. In vitro, the cyclin B-cdc2 complex phosphorylated HEI10 primarily at the NTPVR cell cycle kinase consensus site.
Qiao et al. (2014) showed that the ubiquitin ligase HEI10 is essential for the crossover/noncrossover differentiation process during mammalian recombination. In Hei10-deficient mice, Rnf212 (612041) localized to most recombination sites, and dissociation of both Rnf212 and MutS-gamma (MSH4, 602105 and MSH5, 603382) from chromosomes was blocked. Consequently, recombination was impeded, and crossing over failed. In wildtype mice, Hei10 accumulated at designated crossover sites, suggesting that it also has a late role in implementing crossing over. As with Rnf212, dosage sensitivity for Hei10 indicated that it is a limiting factor for crossing over. Qiao et al. (2014) suggested that SUMO (see 601912) and ubiquitin (see 191339) have antagonistic roles during meiotic recombination that are balanced to effect differential stabilization of recombination factors at crossover and noncrossover sites.
Rao et al. (2017) found that SUMO modification and ubiquitin-proteasome systems regulate the major events of meiotic prophase in mouse. Interdependent localization of SUMO, ubiquitin, and proteasomes along chromosome axes was mediated largely by RNF212 and HEI10, 2 E3 ligases that are also essential for crossover recombination. RNF212-dependent SUMO conjugation effected a checkpoint-like process that stalls recombination by rendering the turnover of a subset of recombination factors dependent on HEI10-mediated ubiquitylation. Rao et al. (2017) proposed that SUMO conjugation establishes a precondition for designating crossover sites via selective protein stabilization. Thus, meiotic chromosome axes are hubs for regulated proteolysis via SUMO-dependent control of the ubiquitin-proteasome system.
Toby et al. (2003) determined that the HEI10 gene contains 3 exons.
Band 12q15 is often rearranged in benign mesenchymal tumors such as uterine leiomyomas (150699), and the HMGIC gene (600698) is present in that region. Mine et al. (2001) identified HEI10 as a fusion partner with HMGIC in a uterine leiomyoma. Radiation hybrid mapping demonstrated that the normal location of HEI10 is 14q11. In the fusion transcript, the first 2 exons of the HMGIC gene, which encode DNA-binding domains, were fused in the 3-prime portion of the HEI10 gene.
By genomic sequence analysis, Toby et al. (2003) mapped the HEI10 gene to chromosome 14q11.1.
Makalowski, W., Zhang, J., Boguski, M. S. Comparative analysis of 1196 orthologous mouse and human full-length mRNA and protein sequences. Genome Res. 6: 846-857, 1996. [PubMed: 8889551] [Full Text: https://doi.org/10.1101/gr.6.9.846]
Mine, N., Kurose, K., Konishi, H., Araki, T., Nagai, H., Emi, M. Fusion of a sequence from HEI10 (14q11) to the HMGIC gene at 12q15 in a uterine leiomyoma. Jpn. J. Cancer Res. 92: 135-139, 2001. [PubMed: 11223542] [Full Text: https://doi.org/10.1111/j.1349-7006.2001.tb01075.x]
Qiao, H., Prasada Rao, H. B. D., Yang, Y., Fong, J. H., Cloutier, J. M., Deacon, D. C., Nagel, K. E., Swartz, R. K., Strong, E., Holloway, J. K., Cohen, P. E., Schimenti, J., Ward, J., Hunter, N. Antagonistic roles of ubiquitin ligase HEI10 and SUMO ligase RNF212 regulate meiotic recombination. Nature Genet. 46: 194-199, 2014. [PubMed: 24390283] [Full Text: https://doi.org/10.1038/ng.2858]
Rao, H. B. D. P., Qiao, H., Bhatt, S. K., Bailey, L. R. J., Tran, H. D., Bourne, S. L., Qui, W., Deshpande, A., Sharma, A. N., Beebout, C. J., Pezza, R. J., Hunter, N. A SUMO-ubiquitin relay recruits proteasomes to chromosome axes to regulate meiotic recombination. Science 355: 403-407, 2017. [PubMed: 28059716] [Full Text: https://doi.org/10.1126/science.aaf6407]
Toby, G. G., Gherraby, W., Coleman, T. R., Golemis, E. A. A novel RING finger protein, human enhancer of invasion 10, alters mitotic progression through regulation of cyclin B levels. Molec. Cell. Biol. 23: 2109-2122, 2003. [PubMed: 12612082] [Full Text: https://doi.org/10.1128/MCB.23.6.2109-2122.2003]