Other entities represented in this entry:
HGNC Approved Gene Symbol: SENP1
Cytogenetic location: 12q13.11 Genomic coordinates (GRCh38): 12:48,042,897-48,106,079 (from NCBI)
The covalent modification of proteins by the small ubiquitin (UBB; 191339)-like protein SUMO (see SUMO1, 601912) is implicated in the regulation of nucleocytoplasmic transport, genomic stability, gene transcription, and other processes. Sumoylation is catalyzed on target lysine residues by a multienzyme process and is reversed by desumoylating enzymes such as SENP1 (Yamaguchi et al., 2005).
By searching an EST database for homologs of yeast Ulp1, followed by PCR of a placenta cDNA library and 3-prime and 5-prime RACE, Gong et al. (2000) cloned SENP1. The deduced 643-amino acid protein contains a C-terminal domain that includes conserved histidine, aspartate, and cysteine residues characteristic of cysteine proteases. SENP1 shares 21% identity with yeast Ulp1.
Gong et al. (2000) determined that the SENP1 gene contains 18 exons and spans 61 kb. Exon 3 contains the translational start codon.
By genomic sequence analysis, Gong et al. (2000) mapped the SENP1 gene to chromosome 12q13.1.
Gong et al. (2000) showed that SENP1 removed the SUMO1 modification from a sumoylated protein in transfected COS cells concomitant with the accumulation of free SUMO1 monomers. It also removed SUMO2 (603042) modifications, but not ubiquitin or NEDD8 (603171) modifications. SENP1 desumoylated the nuclear protein PML (102578), but not RanGAP1 (602362), which resides on the cytoplasmic side of the nuclear pore complex. Since SENP1 was able to remove the SUMO1 modification from RanGAP1 in vitro, Gong et al. (2000) concluded that the inability of SENP1 to desumoylate RanGAP1 in vivo is due to the SENP1 nuclear localization.
Veltman et al. (2005) identified a patient with an infantile sacrococcygeal teratoma and a constitutional t(12;15)(q13;q25) chromosomal translocation, resulting in SENP1/MESDC2 (607783) fusion genes. Both reciprocal SENP1/MESDC2 (SEME) and MESDC2/SENP1 (MESE) fusion genes were transcribed in tumor-derived cells, and their open reading frames encoded aberrant proteins. In contrast to wildtype MESDC2, the translocation-associated SEME protein was no longer targeted to the endoplasmic reticulum, leading to a presumed loss-of-function as a chaperone for the WNT coreceptors LRP5 (603506) and/or LRP6 (603507). SUMO, a posttranslational modifier, plays an important role in several cellular key processes and is cleaved from its substrates by wildtype SENP1. In vitro studies revealed that translocation-associated MESE proteins exhibited desumoylation capacities similar to those observed for wildtype SENP1. Veltman et al. (2005) speculated that spatiotemporal disturbances in desumoylating activities during critical stages of embryonic development might be responsible for teratoma formation. The constitutional t(12;15)(q13;q25) translocation suggested SENP1 and MESDC2 as candidate genes for neonatal/infantile germ cell tumor development.
Xu et al. (2008) found that the activities of SENP1, SENP2 (608261), and Ulp1 were inhibited by oxidation. Peroxide induced the formation of an intermolecular disulfide linkage in SENP1 via the active-site cysteines at positions 603 and 613. This reversible modification, also observed in yeast Ulp1 but not in SENP2, conferred a higher recovery of enzyme activity following inhibition, as well as protection against further irreversible oxidation and enzyme inhibition. In vivo formation of a disulfide-linked SENP1 dimer was also detected in cultured cells in response to oxidative stress. Experiments examining the crystal structures of Ulp1 under increasing oxidation of a catalytic cysteine revealed that Ulp1 was extremely sensitive to mild oxidation, even at the atmospheric oxygen level. Xu et al. (2008) concluded that SENP1 may act as a redox sensor and modulate protein desumoylation and cellular responses to oxidative stress.
Using mechanistic studies in human cells, Yu et al. (2010) found that SENP1 directly desumoylated GATA1 and thereby regulated GATA1 DNA-binding activity, GATA1-dependent EPOR (133171) expression, and erythropoiesis. They concluded that SENP1 promotes GATA1 activation and subsequent erythropoiesis by desumoylating GATA1.
Azad et al. (2016) reprogrammed fibroblasts from chronic mountain sickness (CMS; 616182) and non-CMS individuals living at high altitude in Peru, as well as sea level-dwelling Peruvian controls, and generated induced pluripotent stem cells that were then transformed into erythroid cells. Following exposure of the cells at the embryoid body stage to 5% O2 for 28 days, sea-level controls had a modest (5-fold) increase in expression of the erythroid marker CD235A (GYPA; 617922) and non-CMS individuals had no change in CD235A expression, whereas CMS subjects had a marked (over 50-fold) change in CD235A expression, suggesting a genetically controlled polycythemic response to hypoxia. Knockdown of SENP1 resulted in a marked reduction in CD235A expression in the response of CMS cells to hypoxia. Overexpressing SENP1 in non-CMS cells resulted in a polycythemic phenotype. Expression of BCLXL (BCL2L1; 600039) and, particularly, GATA1 (305371) increased significantly in CMS cells undergoing hypoxia. Sumoylation of GATA1 in CMS cells was much lower than in non-CMS cells. Azad et al. (2016) concluded that GATA1 activation mediated by SENP1 desumoylation is essential for the polycythemic response in CMS. Furthermore, they concluded that the differential expression and responses of GATA1, an essential downstream target of SENP1, and BCLXL are key mechanisms underlying CMS pathology.
For discussion of a possible association between variation in the SENP1 gene and susceptibility to chronic mountain sickness, see 616182.
Yamaguchi et al. (2005) found that homozygous disruption of the Senp1 gene in mice via a retroviral insertional mutation caused embryonic lethality between embryonic days 12.5 and 14.5 due to placental abnormalities. Senp1 -/- embryos showed increased steady-state levels of the sumoylated forms of a number of proteins, including Rangap1 (602362).
Yu et al. (2010) observed erythropoietic defects in fetal liver of Senp1 -/- mice. These defects were accompanied by reduced activity of Gata1 and reduced expression of Gata1 target genes due to accumulation of sumoylated Gata1.
Azad, P., Zhao, H. W., Cabrales, P. J., Ronen, R., Zhou, D., Poulsen, O., Appenzeller, O., Hsiao, Y. H., Bafna, V., Haddad, G. G. Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge's disease. J. Exp. Med. 213: 2729-2744, 2016. [PubMed: 27821551] [Full Text: https://doi.org/10.1084/jem.20151920]
Gong, L., Millas, S., Maul, G. G., Yeh, E. T. H. Differential regulation of sentrinized proteins by a novel sentrin-specific protease. J. Biol. Chem. 275: 3355-3359, 2000. [PubMed: 10652325] [Full Text: https://doi.org/10.1074/jbc.275.5.3355]
Veltman, I. M., Vreede, L. A., Cheng, J., Looijenga, L. H. J., Janssen, B., Schoenmakers, E. F. P. M., Yeh, E. T. H., Geurts van Kessel, A. Fusion of the SUMO/sentrin-specific protease 1 gene SENP1 and the embryonic polarity-related mesoderm development gene MESDC2 in a patient with an infantile teratoma and a constitutional t(12;15)(q13;q25). Hum. Molec. Genet. 14: 1955-1963, 2005. [PubMed: 15917269] [Full Text: https://doi.org/10.1093/hmg/ddi200]
Xu, Z., Lam, L. S. M., Lam, L. H., Chau, S. F., Ng, T. B., Au, S. W. N. Molecular basis of the redox regulation of SUMO proteases: a protective mechanism of intermolecular disulfide linkage against irreversible sulfhydryl oxidation. FASEB J. 22: 127-137, 2008. [PubMed: 17704192] [Full Text: https://doi.org/10.1096/fj.06-7871com]
Yamaguchi, T., Sharma, P., Athanasiou, M., Kumar, A., Yamada, S., Kuehn, M. R. Mutation of SENP1/SuPr-2 reveals an essential role for desumoylation in mouse development. Molec. Cell. Biol. 25: 5171-5182, 2005. [PubMed: 15923632] [Full Text: https://doi.org/10.1128/MCB.25.12.5171-5182.2005]
Yu, L., Ji, W., Zhang, H., Renda, M. J., He, Y., Lin, S., Cheng, E., Chen, H., Krause, D. S., Min, W. SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis. J. Exp. Med. 207: 1183-1195, 2010. [PubMed: 20457756] [Full Text: https://doi.org/10.1084/jem.20092215]