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HGNC Approved Gene Symbol: SENP6
Cytogenetic location: 6q14.1 Genomic coordinates (GRCh38) : 6:75,601,880-75,718,281 (from NCBI)
Ubiquitin-like molecules (UBLs), such as SUMO1 (UBL1; 601912), are structurally related to ubiquitin (191339) and can be ligated to target proteins in a similar manner as ubiquitin. However, covalent attachment of UBLs does not result in degradation of the modified proteins. SUMO1 modification is implicated in the targeting of RANGAP1 (602362) to the nuclear pore complex, as well as in stabilization of I-kappa-B-alpha (NFKBIA; 164008) from degradation by the 26S proteasome. Like ubiquitin, UBLs are synthesized as precursor proteins, with 1 or more amino acids following the C-terminal glycine-glycine residues of the mature UBL protein. Thus, the tail sequences of the UBL precursors need to be removed by UBL-specific proteases, such as SENP6, prior to their conjugation to target proteins (Kim et al., 2000). SENPs also display isopeptidase activity for deconjugation of SUMO-conjugated substrates (Lima and Reverter, 2008).
By screening human brain cDNAs for the potential to encode proteins that are at least 50 kD, Nagase et al. (1998) isolated a partial SUSP1 cDNA, which they called KIAA0797, that lacks 5-prime coding sequence. The deduced partial SUSP1 protein has 1,084 amino acids. RT-PCR followed by ELISA detected SUSP1 expression in all 10 human tissues examined, with highest expression in ovary and lowest expression in spleen.
By 5-prime-anchored PCR using the KIAA0797 cDNA isolated by Nagase et al. (1998), Kim et al. (2000) determined the complete SUSP1 coding sequence. The deduced 1,112-amino acid SUSP1 protein is a cysteine protease containing the conserved histidine, aspartic acid, and cysteine residues of the catalytic triad and the invariant glutamine residue that helps form the oxyanion hole. The sequence similarity of SUSP1 to other known UBL-specific proteases was largely restricted to the active site domains. Recombinant SUSP1 was exclusively localized to the cytoplasm of mammalian cells. Northern blot analysis detected a 4.4-kb SUSP1 transcript in various human tissues. The highest expression of SUSP1 was in reproductive organs, namely testis, ovary, and prostate. SUSP1 was also expressed in colon and peripheral blood leukocytes. Little or no SUSP1 transcripts were detected in brain, liver, lung, kidney, pancreas, spleen, thymus, heart, and skeletal muscle.
Kim et al. (2000) found that recombinant SUSP1 expressed in bacteria efficiently released SUMO1 from a SUMO1-beta-galactosidase fusion protein but not from a RANGAP1-SUMO1 conjugate, suggesting a role for SUSP1 in the generation of mature SUMO1 specifically from its precursor. SUSP1 showed a tight substrate specificity for SUMO1. Based on the SUSP1 expression pattern, Kim et al. (2000) suggested that SUSP1 may play a role in the regulation of SUMO1-mediated cellular processes particularly related to reproduction.
Lima and Reverter (2008) showed that the isolated catalytic domains of SENP6 and SENP7 (612846) could not efficiently process SUMO1, SUMO2 (603042), and SUMO3 (602231) precursors. In contrast, SENP6 and SENP7 exhibited efficient SUMO deconjugation activity, with a preference for substrates containing SUMO2 or SUMO3 over substrates containing SUMO1. SENP6 and SENP7 showed higher rates for deconjugating di- or poly-SUMO2 and -SUMO3 than for deconjugating SUMO2- or SUMO3-conjugated RANGAP1. Lima and Reverter (2008) concluded that the high poly-SUMO2 and -SUMO3 chain deconjugation activities of SENP6 and SENP7 may reflect a preference for flexible isopeptide-linked substrates.
The International Radiation Hybrid Mapping Consortium mapped the SUSP1 gene to chromosome 6 (WI-6806). By genomic sequence analysis, Tagawa et al. (2002) mapped the SUSP1 gene to chromosome 6q13.
HT-1 is a T-cell lymphoma/leukemia cell line with complex cytogenetic aberrations. Tagawa et al. (2002) found that del(6)(q13q21) in HT-1 cells resulted in fusion of nucleotide 551 of the SUSP1 gene to exon 4 of the TCBA1 gene (NKAIN2; 609758). Nucleotides 489 to 509 of SUSP1 were deleted in the chimeric transcript. A frameshift occurred in exon 4 of TCBA1 in the chimeric transcript, resulting in a chimeric protein with a unique truncated C terminus relative to wildtype SUSP1.
Kim, K. I., Baek, S. H., Jeon, Y.-J., Nishimori, S., Suzuki, T., Uchida, S., Shimbara, N., Saitoh, H., Tanaka, K., Chung, C. H. A new SUMO-1-specific protease, SUSP1, that is highly expressed in reproductive organs. J. Biol. Chem. 275: 14102-14106, 2000. [PubMed: 10799485] [Full Text: https://doi.org/10.1074/jbc.275.19.14102]
Lima, C. D., Reverter, D. Structure of the human SENP7 catalytic domain and poly-SUMO deconjugation activities for SENP6 and SENP7. J. Biol. Chem. 283: 32045-32055, 2008. [PubMed: 18799455] [Full Text: https://doi.org/10.1074/jbc.M805655200]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 277-286, 1998. [PubMed: 9872452] [Full Text: https://doi.org/10.1093/dnares/5.5.277]
Tagawa, H., Miura, I., Suzuki, R., Suzuki, H., Hosokawa, Y., Seto, M. Molecular cytogenetic analysis of the breakpoint region at 6q21-22 in T-cell lymphoma/leukemia cell lines. Genes Chromosomes Cancer 34: 175-185, 2002. [PubMed: 11979551] [Full Text: https://doi.org/10.1002/gcc.10057]