Alternative titles; symbols
HGNC Approved Gene Symbol: SUMO1
Cytogenetic location: 2q33.1 Genomic coordinates (GRCh38): 2:202,206,171-202,238,597 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.1 | ?Orofacial cleft 10 | 613705 | Isolated cases | 3 |
SUMO proteins, such as SUMO1, and ubiquitin (see 191339) posttranslationally modify numerous cellular proteins and affect their metabolism and function. However, unlike ubiquitination, which targets proteins for degradation, sumoylation participates in a number of cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability (Su and Li, 2002).
In yeast, the RAD51 (179617)/RAD52 (600392) pathway is involved in DNA recombination and the repair of double-strand breaks in DNA. Shen et al. (1996) used the yeast 2-hybrid method to identify a novel protein that interacts with RAD51 and RAD52. Sequence analysis of the corresponding gene, termed UBL1, revealed that the gene encodes a 101-amino acid polypeptide with homology to ubiquitin and other ubiquitin-like proteins. The closest homolog of this protein is yeast SMT3, which functionally associates with MIF2, a yeast centromere protein involved in chromosome segregation at mitosis. Northern blot analysis revealed that the UBL1 gene was expressed in all tissues tested, with the highest expression level in testis.
By screening a human B-cell cDNA library for PML (102578)-interacting clones, Boddy et al. (1996) cloned PIC1. The deduced protein shows 52% identity with the S. cerevisiae Smt3 protein. Transient transfection of mouse fibroblasts resulted in a nuclear staining pattern coincident with expression of endogenous mouse Pml. Cotransfection of PIC1 and PML produced a completely overlapping staining pattern.
FAS/APO1 (134637) and TNFR1 (191190) share a common signaling motif, called the 'death domain,' in their cytoplasmic tails. Deletion or mutation of this domain abolishes the ability of these receptors to transduce the apoptosis signal. Death domain-associated proteins, such as FADD/MORT1 (602457) and RIP (600862), are essential for apoptosis induction. Okura et al. (1996) used a yeast 2-hybrid system to identify human sentrin (SMT3H3), which interacts specifically with the death domains of the signal-competent forms of FAS/APO1 or TNFR1 but not with the death domains of FADD/MORT1 or CD40 (109535). The authors demonstrated that sentrin provides protection against both anti-FAS/APO1- and TNF-induced cell death. The deduced SMT3H3 protein has 18% sequence identity to human ubiquitin and 50% identity to S. cerevisiae Smt3.
Lapenta et al. (1997) isolated an SMT3H3 cDNA as an expressed sequence tag that encodes a protein with 47% identity to SMT3H1 (602231).
Howe et al. (1998) cloned mouse Pic1 from a brain cDNA library and found that there are 2 polyadenylation signals in the 3-prime UTR. They noted that the human PIC1 cDNA cloned by Boddy et al. (1996) has 3 polyadenylation signals. The deduced mouse protein contains 101 amino acids and is identical to human PIC1. Northern blot analysis detected a 1.3-kb transcript in all mouse tissues examined.
Su and Li (2002) determined that all SUMO proteins from yeast to human share the conserved ubiquitin domain and the C-terminal diglycine cleavage/attachment site. The most prominent difference between SUMO proteins and ubiquitin is the presence of highly variable N-terminal extensions in the SUMO proteins. Human SUMO1 shares 44% amino acid identity with SUMO2 (603042) and SUMO3 (602231). RT-PCR of HeLa, kidney, and neuronal cell lines indicated that expression of SUMO1 is more abundant than expression of SUMO2 or SUMO3.
Activation of NF-kappa-B is achieved by ubiquitination and proteasome-mediated degradation of I-kappa-B-alpha (164008). Desterro et al. (1998) detected modified I-kappa-B-alpha, conjugated to the small ubiquitin-like protein SUMO1, which is resistant to signal-induced degradation. Overexpression of SUMO1 inhibits signal-induced activation of NF-kappa-B-dependent transcription. SUMO1 modification of I-kappa-B-alpha is inhibited by phosphorylation. Thus, while ubiquitination targets proteins for rapid degradation, SUMO1 modification acts antagonistically to generate proteins resistant to degradation.
Boddy et al. (1996) demonstrated that PIC1 interacts with the PML component of the multiprotein complex that is disrupted in acute promyelocytic leukemia.
Many antibiotics, anticancer drugs, toxins, carcinogens, and physiologic stresses abort the catalytic cycles of topoisomerases (see TOP1, 126420), resulting in topoisomerase-mediated DNA damage. Mao et al. (2000) showed that camptothecin, a TOP1-specific poison, can induce rapid and extensive conjugation of SUMO1 to human DNA. This and other observations suggested that SUMO1 may be involved in the repair of TOP1-mediated DNA damage.
Su and Li (2002) found that expression of epitope-labeled SUMO1 in baby hamster fibroblasts resulted in its conjugation to many cellular proteins between 76 and 170 kD. No free SUMO1 was observed, in contrast to the results following SUMO2 and SUMO3 transfection. Immunofluorescent staining detected SUMO1 predominantly on nuclear membranes. SUMO2 and SUMO3 were detected on nuclear bodies and in the cytoplasm, respectively.
SUMO uses a ubiquitin conjugation system to counteract the effects of ubiquitination. Ubiquitin and SUMO compete for modification of proliferating cell nuclear antigen (PCNA; 176740), an essential processivity factor for DNA replication and repair. Whereas multiubiquitination is mediated by components of the RAD6 pathway (312180, 179095) and promotes error-free repair, SUMO modification is associated with replication. Stelter and Ulrich (2003) demonstrated that RAD6-mediated monoubiquitination of PCNA activates translesion DNA synthesis by the damage-tolerant polymerases eta (603968) and zeta (602776) in yeast. Moreover, polymerase zeta is differentially affected by monoubiquitin and SUMO modification of PCNA. Whereas ubiquitination is required for damage-induced mutagenesis, both SUMO and monoubiquitin contribute to spontaneous mutagenesis in the absence of DNA damage. Stelter and Ulrich (2003) concluded that their data assigned a function to SUMO during S phase and demonstrated how ubiquitin and SUMO, by regulating the accuracy of replication and repair, contribute to overall genomic stability.
Song et al. (2004) identified a consensus SUMO-binding motif (V/I-x-V/I-V/I) that was present in nearly all proteins involved in SUMO-dependent processes.
By yeast 2-hybrid analysis of a human fetal brain cDNA library, followed by coimmunoprecipitation analysis, Kunapuli et al. (2006) found that ZNF198 (ZMYM2; 602221) was covalently modified by SUMO1. Confocal microscopy showed that a proportion of ZNF198 colocalized with SUMO1 and PML in PML nuclear bodies, and coimmunoprecipitation analysis revealed that all 3 proteins resided in a protein complex. Mutation of the SUMO1-binding site of ZNF198 resulted in degradation of ZNF198, nuclear dispersal of PML, and loss of punctate PML nuclear bodies. Kunapuli et al. (2006) found that the MDA-MB-157 breast cancer cell line, which has a deletion in chromosome 13q11 encompassing the ZNF198 gene, lacked PML nuclear bodies, although PML protein levels appeared normal. The fusion protein ZNF198/FGFR1 (136350), which occurs in atypical myeloproliferative disease (613523) and lacks the SUMO1-binding site of ZNF198, could dimerize with wildtype ZNF198 and disrupt its function. Expression of ZNF198/FGFR1 disrupted PML sumoylation and nuclear body formation and resulted in cytoplasmic localization of SUMO1. Kunapuli et al. (2006) concluded that sumoylation of ZNF198 is required for PML nuclear body formation.
Martin et al. (2007) reported that in rat hippocampal neurons multiple sumoylation targets are present at synapses and demonstrated that the kainate receptor subunit GluR6 (138244) is a SUMO substrate. Sumoylation of GluR6 regulated endocytosis of the kainate receptor and modified synaptic transmission. GluR6 exhibited low levels of sumoylation under resting conditions and was rapidly SUMOylated in response to a kainate but not an N-methyl-D-aspartate (NMDA) treatment. Reducing GluR6 sumoylation using the SUMO-specific isopeptidase SENP-1 prevented kainate-evoked endocytosis of the kainate receptor. Furthermore, a mutated non-sumoylatable form of GluR6 was not endocytosed in response to kainate in COS-7 cells. Consistent with this, electrophysiologic recordings in hippocampal slices demonstrated that kainate receptor-mediated excitatory postsynaptic currents were decreased by sumoylation and enhanced by desumoylation. Martin et al. (2007) concluded that their data revealed a previously unsuspected role for SUMO in the regulation of synaptic function.
Alkuraya et al. (2006) found Sumo1 to be expressed on mouse embryonic day 13.5 in the upper lip, primary palate, and medial edge epithelia of the secondary palate. At embryonic day 14.5, expression of Sumo1 could be seen in the medial edge epithelial seam using section in situ hybridization.
Andreou et al. (2007) found that TBX22 (300307) is a target for SUMO1 and that this modification is required for repression of TBX22 activity. Loss of SUMO1 modification was consistently found in all pathogenic X-linked cleft palate (CPX; 303400) missense mutations. This implied a general mechanism linking the loss of SUMO conjugation to the loss of TBX22 function. Orofacial clefts are well known for their complex etiology and variable penetrance, including both genetic and environmental risk factors. The sumoylation process is also subject to and profoundly affected by similar environmental stresses, as listed by Andreou et al. (2007). Thus, they suggested that SUMO modification may represent a common pathway that regulates normal craniofacial development and is involved in the pathogenesis of both mendelian and idiopathic forms of orofacial clefting.
Morris et al. (2009) reported that BRCA1 (113705) is modified by SUMO in response to genotoxic stress, and colocalizes at sites of DNA damage with SUMO1, SUMO2 (603042)/SUMO3 (602231), and the SUMO conjugating-enzyme Ubc9 (601661). PIAS SUMO E3 ligases (PIAS1; 603566 and PIAS4 605989) colocalize with and modulate SUMO modification of BRCA1, and are required for BRCA1 ubiquitin ligase activity in cells. In vitro, SUMO modification of the BRCA1/BARD1 (601593) heterodimer greatly increases its ligase activity, identifying it as a SUMO-regulated ubiquitin ligase. Furthermore, PIAS SUMO ligases are required for complete accumulation of double-stranded DNA damage repair proteins subsequent to RNF8 (611685) accrual, and for proficient double-strand break repair. Morris et al. (2009) concluded that the sumoylation pathway plays a significant role in mammalian DNA damage response.
Galanty et al. (2009) demonstrated that SUMO1, SUMO2, and SUMO3 accumulate at double-strand DNA break sites in mammalian cells, with SUMO1 and SUMO2/3 accrual requiring the E3 ligase enzymes PIAS4 and PIAS1. Galanty et al. (2009) also established that PIAS1 and PIAS4 are recruited to damage sites via mechanisms requiring their SAP domains, and are needed for the productive association of 53BP1 (605230), BRCA1, and RNF168 (612688) with such regions. Furthermore, Galanty et al. (2009) showed that PIAS1 and PIAS4 promote double-strand break repair and confer ionizing radiation resistance. Finally, the authors established that PIAS1 and PIAS4 are required for effective ubiquitin adduct formation mediated by RNF8, RNF168, and BRCA1 at sites of DNA damage. Galanty et al. (2009) concluded that their findings identified PIAS1 and PIAS4 as components of the DNA damage response and revealed how protein recruitment to DNA double-strand break sites is controlled by coordinated sumoylation and ubiquitylation.
Kho et al. (2011) showed that SERCA2a (108740) is SUMOylated at lys480 and lys585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells. The level of SUMO1 and SUMOylation of SERCA2a itself were greatly reduced in failing hearts. SUMO1 restitution by adeno-associated-virus-mediated gene delivery maintained the protein abundance of SERCA2a and markedly improved cardiac function in mice with heart failure. This effect was comparable to SERCA2A gene delivery. Moreover, SUMO1 overexpression in isolated cardiomyocytes augmented contractility and accelerated calcium decay. Transgene-mediated SUMO1 overexpression rescued cardiac dysfunction induced by pressure overload concomitantly with increased SERCA2a function. By contrast, downregulation of SUMO1 using small hairpin RNA accelerated pressure overload-induced deterioration of cardiac function and was accompanied by decreased SERCA2a function. However, knockdown of SERCA2a resulted in severe contractile dysfunction both in vitro and in vivo, which was not rescued by overexpression of SUMO1. Kho et al. (2011) concluded that, taken together, their data showed that SUMOylation is a critical posttranslational modification that regulates SERCA2a function, and provided a platform for the design of novel therapeutic strategies for heart failure.
Su and Li (2002) reported that the human SUMO1 gene contains 5 exons and spans about 32 kb.
Howe et al. (1998) determined that the mouse Sumo1 gene contains 5 exons. The promoter has no TATA box.
Crystal Structure
Reverter and Lima (2005) described the 3.0-angstrom crystal structure of a 4-protein complex of UBC9 (601661), a NUP358/RANBP2 (601181) E3 ligase domain (IR1-M), and SUMO1 conjugated to the carboxy-terminal domain of RANGAP1 (602362). Structural insights, combined with biochemical and kinetic data obtained with additional substrates, supported a model in which NUP358/RANBP2 acts as an E3 by binding both SUMO and UBC9 to position the SUMO-E2-thioester in an optimal orientation to enhance conjugation.
Baba et al. (2005) reported the crystal structure of the central region of human TDG (601423) conjugated to SUMO1 at 2.1-angstrom resolution. The structure revealed a helix protruding from the protein surface, which presumably interferes with the product DNA and thus promotes the dissociation of TDG from the DNA molecule. This helix is formed by covalent and noncovalent contacts between TDG and SUMO1. The noncovalent contacts are also essential for release from the product DNA, as verified by mutagenesis.
Shen et al. (1996) used PCR and FISH to map the UBL1 gene to chromosome 2q32.2-q33. Observation of PCR products and fluorescent bands from other chromosomes suggested that UBL1 may be one of a family of related proteins. Howe et al. (1998) identified SUMO1 pseudogenes on chromosomes 1, 5, and 19. Su and Li (2002) reported that the human SUMO1 gene has 8 pseudogenes.
By FISH, Howe et al. (1998) mapped the mouse Sumo1 gene to chromosome 1C2-C3, a region that shows homology of synteny to human chromosome 2. They identified 2 mouse Sumo1 pseudogenes.
Alkuraya et al. (2006) identified a 5-year-old Caucasian girl with a unilateral cleft lip and palate (primary and secondary) who was otherwise phenotypically normal (OFC10; 613705). Her karyotype was 46,XX,t(2;8)(q33.1;q24.3), and array CGH analysis was normal. Alkuraya et al. (2006) showed that this balanced translocation disrupted the SUMO1 gene, leading to haploinsufficiency confirmed by RNA and protein studies.
Alkuraya et al. (2006) generated mice carrying a Sumo1 hypomorphic allele and found that 4 of 46 pups (8.7%) had cleft palate or oblique facial cleft, compared with none in more than 100 wildtype mice. In addition, the genotype distribution from heterozygous crosses at P1 (1:1.15:0.75) deviated from the expected 1:2:1. Both embryonic demise between embryonic days 13.5 and 18.5 and immediate postnatal demise were noted for Sumo1 hetero- and homozygotes, indicating that Sumo1 is required for developmental functions besides palatogenesis. Alkuraya et al. (2006) found that heterozygotes for both Sumo1 and Eya1 (601653) haploinsufficiency had a much higher incidence of cleft palate (36%) than either Sumo1-haploinsufficient heterozygotes (8.7%) or Eya1-deficient heterozygotes (0.0%). Additionally, Alkuraya et al. (2006) found that Eya1 is a substrate for sumoylation with Sumo1 in vivo.
In a 5-year-old girl with unilateral cleft lip and palate (primary and secondary) and no other phenotypic abnormalities (OFC10; 613705), Alkuraya et al. (2006) found a balanced translocation between chromosomes 2 and 8 (46,XX,t(2;8)(q33.1;q24.3)). Additional studies showed that the breakpoint occurred in the SUMO1 gene and resulted in haploinsufficiency confirmed by RNA and protein assays.
Alkuraya, F. S., Saadi, I., Lund, J. L., Turbe-Doan, A., Morton, C. C., Maas, R. L. SUMO1 haploinsufficiency leads to cleft lip and palate. Science 313: 1751 only, 2006. [PubMed: 16990542] [Full Text: https://doi.org/10.1126/science.1128406]
Andreou, A. M., Pauws, E., Jones, M. C., Singh, M. K., Bussen, M., Doudney, K., Moore, G. E., Kispert, A., Brosens, J. J., Stanier, P. TBX22 missense mutations found in patients with X-linked cleft palate affect DNA binding, sumoylation, and transcriptional repression. Am. J. Hum. Genet. 81: 700-712, 2007. [PubMed: 17846996] [Full Text: https://doi.org/10.1086/521033]
Baba, D., Maita, N., Jee, J.-G., Uchimura, Y., Saitoh, H., Sugasawa, K., Hanaoka, F., Tochio, H., Hiroaki, H., Shirakawa, M. Crystal structure of thymine DNA glycosylase conjugated to SUMO-1. (Letter) Nature 435: 979-982, 2005. [PubMed: 15959518] [Full Text: https://doi.org/10.1038/nature03634]
Boddy, M. N., Howe, K., Etkin, L. D., Solomon, E., Freemont, P. S. PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia. Oncogene 13: 971-982, 1996. [PubMed: 8806687]
Desterro, J. M. P., Rodriguez, M. S., Hay, R. T. SUMO-1 modification of I-kappa-B-alpha inhibits NF-kappa-B activation. Molec. Cell 2: 233-239, 1998. [PubMed: 9734360] [Full Text: https://doi.org/10.1016/s1097-2765(00)80133-1]
Galanty, Y., Belotserkovskaya, R., Coates, J., Polo, S., Miller, K. M., Jackson, S. P. Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks. Nature 462: 935-939, 2009. [PubMed: 20016603] [Full Text: https://doi.org/10.1038/nature08657]
Howe, K., Williamson, J., Boddy, N., Sheer, D., Freemont, P., Solomon, E. The ubiquitin-homology gene PIC1: characterization of mouse (Pic1) and human (UBL1) genes and pseudogenes. Genomics 47: 92-100, 1998. [PubMed: 9465300] [Full Text: https://doi.org/10.1006/geno.1997.5091]
Kho, C., Lee, A., Jeong, D., Oh, J. G., Chaanine, A. H., Kizana, E., Park, W. J., Hajjar, R. J. SUMO1-dependent modulation of SERCA2a in heart failure. Nature 477: 601-605, 2011. [PubMed: 21900893] [Full Text: https://doi.org/10.1038/nature10407]
Kunapuli, P., Kasyapa, C. S., Chin, S.-F., Caldas, C., Cowell, J. K. ZNF198, a zinc finger protein rearranged in myeloproliferative disease, localizes to the PML nuclear bodies and interacts with SUMO-1 and PML. Exp. Cell Res. 312: 3739-3751, 2006. [PubMed: 17027752] [Full Text: https://doi.org/10.1016/j.yexcr.2006.06.037]
Lapenta, V., Chiurazzi, P., van der Spek, P., Pizzuti, A., Hanaoka, F., Brahe, C. SMT3A, a human homologue of the S. cerevisiae SMT3 gene, maps to chromosome 21qter and defines a novel gene family. Genomics 40: 362-366, 1997. [PubMed: 9119407] [Full Text: https://doi.org/10.1006/geno.1996.4556]
Mao, Y., Sun, M., Desai, S. D., Liu, L. F. SUMO-1 conjugation to topoisomerase I: a possible repair response to topoisomerase-mediated DNA damage. Proc. Nat. Acad. Sci. 97: 4046-4051, 2000. [PubMed: 10759568] [Full Text: https://doi.org/10.1073/pnas.080536597]
Martin, S., Nishimune, A., Mellor, J. R., Henley, J. M. SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature 447: 321-325, 2007. [PubMed: 17486098] [Full Text: https://doi.org/10.1038/nature05736]
Morris, J. R., Boutell, C., Keppler, M., Densham, R., Weekes, D., Alamshah, A., Butler, L., Galanty, Y., Pangon, L., Kiuchi, T., Ng, T., Solomon, E. The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress. Nature 462: 886-890, 2009. [PubMed: 20016594] [Full Text: https://doi.org/10.1038/nature08593]
Okura, T., Gong, L., Kamitani, T., Wada, T., Okura, I., Wei, C.-F., Chang, H.-M., Yeh, E. T. H. Protection against Fas/APO-1- and tumor necrosis factor-mediated cell death by a novel protein, sentrin. J. Immun. 157: 4277-4281, 1996. [PubMed: 8906799]
Reverter, D., Lima, C. D. Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. (Letter) Nature 435: 687-692, 2005. [PubMed: 15931224] [Full Text: https://doi.org/10.1038/nature03588]
Shen, Z., Pardington-Purtymun, P. E., Comeaux, J. C., Moyzis, R. K., Chen, D. J. UBL1, a human ubiquitin-like protein associating with human RAD51/RAD52 proteins. Genomics 36: 271-279, 1996. [PubMed: 8812453] [Full Text: https://doi.org/10.1006/geno.1996.0462]
Song, J., Durrin, L. K., Wilkinson, T. A., Krontiris, T. G., Chen, Y. Identification of a SUMO-binding motif that recognizes SUMO-modified proteins. Proc. Nat. Acad. Sci. 101: 14373-14378, 2004. [PubMed: 15388847] [Full Text: https://doi.org/10.1073/pnas.0403498101]
Stelter, P., Ulrich, H. D. Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation. Nature 425: 188-191, 2003. [PubMed: 12968183] [Full Text: https://doi.org/10.1038/nature01965]
Su, H.-L., Li, S. S.-L. Molecular features of human ubiquitin-like SUMO genes and their encoded proteins. Gene 296: 65-73, 2002. [PubMed: 12383504] [Full Text: https://doi.org/10.1016/s0378-1119(02)00843-0]