Alternative titles; symbols
HGNC Approved Gene Symbol: SUN1
Cytogenetic location: 7p22.3 Genomic coordinates (GRCh38): 7:815,557-874,934 (from NCBI)
SUN1 and SUN2 (613569) are inner nuclear membrane (INM) proteins that play a major role in nuclear-cytoplasmic connection by formation of a 'bridge' across the nuclear envelope, known as the LINC complex, via interaction with the conserved luminal KASH domain of nesprins (e.g., SYNE1; 608441) located in the outer nuclear membrane (ONM). The LINC complex provides a direct connection between the nuclear lamina and the cytoskeleton, which contributes to nuclear positioning and cellular rigidity (summary by Haque et al., 2010).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned UNC84A, which they called KIAA0810. The deduced protein contains 824 amino acids. UNC84A shares about 32% identity over 191 amino acids with Sad1 of Saccharomyces pombe. RT-PCR ELISA revealed weak to moderate expression in most tissues examined. Highest expression was detected in heart, skeletal muscle, kidney, and ovary, and weakest expression was detected in spleen.
By searching databases for homologs of C. elegans Unc84, followed by 5-prime RACE of a brain cDNA library, Malone et al. (1999) cloned human SUN1 and SUN2. The predicted proteins contain 824 and 724 amino acids, respectively, and their C termini share homology with the C termini of C. elegans Unc84 and S. pombe Sad1. Both SUN1 and SUN2 contain a transmembrane region.
Using a yeast 2-hybrid screen with Trax (602964) as bait, Bray et al. (2002) cloned Unc84a, which they designated Sun1, from a mouse testis cDNA library. The deduced protein contains 310 amino acids. Overall the mouse and human proteins share 75% homology, and they share 89% homology in the C-terminal Sad1/Unc84 (SUN) domain. Northern blot analysis of mouse tissues detected a 4.3-kb transcript in all tissues examined, with highest levels in heart, brain, and testis, and a 2.5-kb transcript only in testis. Northern blot analysis of isolated testicular germ cells detected the 4.3-kb transcript in pachytene spermatocytes and the 2.5-kb transcript primarily in postmeiotic cells. Unc84a transfected into NIH-3T3 mouse fibroblasts showed 2 patterns of distribution. One pattern was predominantly cytoplasmic with perinuclear accumulation, and the other exhibited both nuclear and cytoplasmic staining, but no accumulation in the nucleoli. Bray et al. (2002) noted that these expression profiles may reflect regulation of expression during the cell cycle, since the transfected cells were not synchronized.
By peptide mass fingerprint spectra, Dreger et al. (2001) identified Unc84a in a TX100-resistant fraction of nuclear envelope proteins isolated from a mouse neuroblastoma cell line. Mouse Unc84a contains a C2H2 zinc finger domain and 3 to 4 putative transmembrane segments. The apparent molecular mass of mouse Unc84a is about 100 kD. Indirect immunofluorescence of transiently transfected COS-7 cells detected Unc84a fluorescence in a rim-like pattern around the nucleus, typical for integral inner nuclear membrane proteins.
By immunofluorescence analysis, Ding et al. (2007) found that the distribution of Sun1 changed during development of mouse spermatids. In primary spermatocytes, but not in round spermatids, Sun1 colocalized with telomeres. Sun1 associated with chromosome ends from early leptotene stage to diplotene stage, including homolog pairing, synapsis, and desynapsis, but it was absent from telomeres during diakinesis.
Using immunofluorescence analysis, Gob et al. (2010) found that Sun1 was expressed in all spermatogenic stages in mice. In spermatids, Sun1 initially displayed dual localization to the posterior and anterior poles, but as differentiation progressed, it accumulated at the anterior pole. Using RT-PCR, Gob et al. (2010) identified a novel Sun1 variant, Sun1-eta, that lacks exons 7 through 10. RT-PCR and immunoblot analyses showed that Sun1-eta was expressed in mouse testis only and was exclusively expressed in postmeiotic stages of sperm development.
By yeast 2-hybrid analysis and in vitro binding assays, Bray et al. (2002) determined that the C terminus of Unc84a interacts directly with Trax.
Haque et al. (2010) stated that SUN1 and SUN2 interact with lamin A (LMNA; 150330) and that LMNA is required for the nuclear envelope localization of SUN2, but not SUN1. By immunoprecipitation of transfected human osteosarcoma cells and mouse fibroblasts, followed by in vitro pull-down assays and immunofluorescence microscopy, Haque et al. (2010) identified emerin (EMD; 300384) and short isoforms of nesprin-2 (SYNE2; 608442) as novel nucleoplasmic binding partners of mouse Sun1 and human SUN2. Emerin and nesprin-2 had overlapping binding sites, distinct from the LMNA-binding site, in Sun1 and SUN2. LMNA mutations associated with Emery-Dreifuss muscular dystrophy-2 (EDMD2; 181350) and Hutchinson-Gilford progeria syndrome (HGPS; 176670) disrupted interaction of LMNA with Sun1 and SUN2. Nuclear localization of SUN1 and SUN2 was not impaired in EDMD2 or HGPS cell lines. Expression of SUN1, but not SUN2, at the nuclear envelope was enhanced in some HGPS cells, likely due to increased interaction of SUN1 with accumulated prelamin A. Haque et al. (2010) proposed that different perturbations in LMNA-SUN protein interactions may underlie the opposing effects of EDMD and HGPS mutations on nuclear and cellular mechanics.
Gob et al. (2010) found that formation of mouse sperm head involved assembly and different polarization of 2 spermiogenesis-specific LINC complexes. One LINC complex formed through interaction of Sun3 (618984) and nesprin-1 and polarized to the posterior pole of the spermatid nuclear envelope. The other LINC complex was nonnuclear and formed through interaction of Sun1-eta and nesprin-3 (SYNE3; 610861) and localized to the anterior pole of the spermatid nucleus. The authors proposed that the 2 LINC complexes connect the differentiating spermatid nucleus to surrounding cytoskeletal structures to enable its well-directed shaping and elongation.
Chen et al. (2012) showed that cells from Lmna -/- mice, which represent EDMD2, cells from Lmna(L530P/L530P) mice, which represent HGPS, and cells from HGPS patients all had overaccumulation of the inner nuclear envelope SUN1 protein. In wildtype cells, Lmna and Sun1 colocalized at the nuclear envelope. In Lmna -/- cells, larger amounts of Sun1 were found at the nuclear envelope and also in the Golgi. The larger amounts of Sun1 appeared to result from reduced protein turnover. Transfection of increasing amounts of mouse Sun1 into Lmna-null/Sun1-null murine cells resulted in increased prevalence of nuclear herniations and apoptosis, and the herniations appeared to result from Sun1 accumulation in the Golgi. Loss of the Sun1 gene in both mouse models extensively rescued cellular, tissue, organ, and life span abnormalities. Similarly, knockdown of overaccumulated SUN1 protein in primary human HGPS cells corrected nuclear defects and cellular senescence. The findings indicated that accumulation of SUN1 is a common pathogenetic event in these disorders.
By radiation hybrid analysis, Nagase et al. (1998) mapped the UNC84A gene to chromosome 7.
Hartz (2013) mapped the SUN1 gene to chromosome 7p22.3 based on an alignment of the SUN1 sequence (GenBank AB018353) with the genomic sequence (GRCh37).
Ding et al. (2007) obtained Sun1-null mouse embryos in the expected mendelian ratio. Both male and female Sun1-null mice developed normally, but they were sterile. Histologic examination showed that germ cells were largely depleted in seminiferous tubules of Sun1-null mice. Spermatids and spermatozoa were completely absent, and only abnormal spermatocyte-like cells accumulated in some tubules. TUNEL staining revealed that massive apoptosis accounted for the absence of spermatids and spermatozoa in Sun1-null testis.
Lei et al. (2009) found that anchorage of skeletal muscle nuclei at neuromuscular junctions was partially disrupted in Sun1-null mice, but not in Sun2-null mice. Anchorage of nonsynaptic nuclei was normal in both Sun1-null mice and Sun2-null mice. Sun1/Sun2 double-knockout mice died soon after birth, with enhanced loss of synaptic nuclei, disrupted organization of nonsynaptic nuclei, and mislocalization of Syne1 at synaptic junctions. Disruption of 3 or all 4 wildtype Sun1 and Sun2 alleles revealed a gene dosage effect on synaptic nuclear anchorage. Lei et al. (2009) concluded that SUN1 and SUN2 have partially redundant functions on synaptic nuclear anchorage in skeletal muscle fibers.
Zhang et al. (2009) showed that Sun1 and Sun2 double-knockout (Sun1/2 DKO) mice and Syne1 and Syne2 double-knockout (Syne1/2 DKO) mice had similar defects in brain development. Sun1/2 DKO and Syne1/2 DKO brains were small and showed defective laminary structures in many brain regions. Examination of neocortex revealed failure of radial neuronal migration, but not tangential migration of interneurons, in both Sun1/2 DKO and Syne1/2 DKO mice. Intracellular movement of nuclei is a prerequisite for proper neuron migration and development, and Zhang et al. (2009) found that Sun1 and Sun2 anchored Syne2 to the nuclear envelope, while Syne1 and Syne2 connected the nuclear envelope to the microtubule network, permitting nuclear movement. Zhang et al. (2009) concluded that a complex made up of SUN1, SUN2, SYNE1, and SYNE2 is required for neuronal nuclear movement and for neuronal migration and development.
By measuring auditory brainstem responses, Horn et al. (2013) found that homozygous deletion of Sun1 or the outer nuclear membrane LINC subunit Nesp4 (SYNE4; 615535) in mice resulted in a similar phenotype characterized by progressive hearing loss. Hearing loss was concomitant with redistribution of nuclei from the base of cochlear outer hair cells to a more apical position and outer hair cell degeneration. Sun1 -/- mice also showed loss of Nesp4 from the nuclear envelope of cochlear outer hair cells. Horn et al. (2013) concluded that the LINC proteins NESP4 and SUN1 are necessary for viability and normal morphology of cochlear outer hair cells and maintenance of normal hearing.
Bray, J. D., Chennathukuzhi, V. M., Hecht, N. B. Identification and characterization of cDNAs encoding four novel proteins that interact with translin associated factor-X. Genomics 79: 799-808, 2002. [PubMed: 12036294] [Full Text: https://doi.org/10.1006/geno.2002.6779]
Chen, C.-Y., Chi, Y.-H., Mutalif, R. A., Starost, M. F., Myers, T. G., Anderson, S. A., Stewart, C. L., Jeang, K.-T. Accumulation of the inner nuclear envelope protein Sun1 is pathogenic in progeric and dystrophic laminopathies. Cell 149: 565-577, 2012. [PubMed: 22541428] [Full Text: https://doi.org/10.1016/j.cell.2012.01.059]
Ding, X., Xu, R., Yu, J., Xu, T., Zhuang, Y., Han, M. SUN1 is required for telomere attachment to nuclear envelope and gametogenesis in mice. Dev. Cell 12: 863-872, 2007. [PubMed: 17543860] [Full Text: https://doi.org/10.1016/j.devcel.2007.03.018]
Dreger, M., Bengtsson, L., Schoneberg, T., Otto, H., Hucho, F. Nuclear envelope proteomics: novel integral membrane proteins of the inner nuclear membrane. Proc. Nat. Acad. Sci. 98: 11943-19948, 2001. [PubMed: 11593002] [Full Text: https://doi.org/10.1073/pnas.211201898]
Gob, E., Schmitt, J., Benavente, R., Alsheimer, M. Mammalian sperm head formation involves different polarization of two novel LINC complexes. PLoS One 5: e12072, 2010. Note: Electronic Article. [PubMed: 20711465] [Full Text: https://doi.org/10.1371/journal.pone.0012072]
Haque, F., Mazzeo, D., Patel, J. T., Smallwood, D. T., Ellis, J. A., Shanahan, C. M., Shackleton, S. Mammalian SUN protein interaction networks at the inner nuclear membrane and their role in laminopathy disease processes. J. Biol. Chem. 285: 3487-3498, 2010. [PubMed: 19933576] [Full Text: https://doi.org/10.1074/jbc.M109.071910]
Hartz, P. A. Personal Communication. Baltimore, Md. 11/19/2013.
Horn, H. F., Brownstein, Z., Lenz, D. R., Shivatzki, S., Dror, A. A., Dagan-Rosenfeld, O., Friedman, L. M., Roux, K. J., Kozlov, S., Jeang, K.-T., Frydman, M., Burke, B., Stewart, C. L., Avraham, K. B. The LINC complex is essential for hearing. J. Clin. Invest. 123: 740-750, 2013. [PubMed: 23348741] [Full Text: https://doi.org/10.1172/JCI66911]
Lei, K., Zhang, X., Ding, X., Guo, X., Chen, M., Zhu, B., Xu, T., Zhuang, Y., Xu, R., Han, M. SUN1 and SUN2 play critical but partially redundant roles in anchoring nuclei in skeletal muscle cells in mice. Proc. Nat. Acad. Sci. 106: 10207-10212, 2009. [PubMed: 19509342] [Full Text: https://doi.org/10.1073/pnas.0812037106]
Malone, C. J., Fixsen, W. D., Horvitz, H. R., Han, M. UNC-84 localizes to the nuclear envelope and is required for nuclear migration and anchoring during C. elegans development. Development 126: 3171-3181, 1999. [PubMed: 10375507] [Full Text: https://doi.org/10.1242/dev.126.14.3171]
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]
Zhang, X., Lei, K., Yuan, X., Wu, X., Zhuang, Y., Xu, T., Xu, R., Han, M. SUN1/2 and Syne/Nesprin-1/2 complexes connect centrosome to the nucleus during neurogenesis and neuronal migration in mice. Neuron 64: 173-187, 2009. [PubMed: 19874786] [Full Text: https://doi.org/10.1016/j.neuron.2009.08.018]