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HOME :: CHAPTER 19 :: PROTEINS INVOLVED IN MEIOSIS :: PROTEINS INVOLVED IN THE SYNAPTONEMAL COMPLEX |
Proteins Involved in the Synaptonemal Complex
The proteins involved in homologous pairing and the formation of the synaptonemal complex are beginning to be identified. Interestingly, the proteins in yeast—where they are most easily identified—do not seem to be homologous to those of animals. While the proteins involved in recombination appear to be very similar, the proteins involved in bringing the chromosomes together during the first meiotic division appear to be different (McKim and Hayashi-Hagihara 1998).
Yeast
In yeast, it is thought that the first events involve searching for double-stranded chromosome breaks where repair enzymes could initiate recombination. The linkage would first be a loose one based on the regions of recombination. Later, a synaptonemal complex would form to zip the chromosomes together (see Chua and Roeder 1998). Some of the best studied proteins involved in homologous pairing are studied in yeast. Yeast mutants can be screened for those that cannot undergo meiosis. Once the mutants are isolated, scientists can identify the stage at which meiosis is blocked and can isolate the gene responsible. The Zip2 protein appears to be an initiator of synapsis that recruits the synaptonemal complex proteins to the chromosomes (Chua and Roeder 1998). Zip2 is only seen in meiotic cells, and it is thought that Zip2 brings these proteins to the sites of chromatin breaks. Zip2 mutants are characterized by being homologously paired, but not bound by a synaptonemal complex. The Zip1 protein, however, is part of the synaptonemtal complex. It is thought to form dimers that span the complex, its amino termini in the central region, and its carboxyl termini in the lateral elements of the complex (Dong and Roeder 2000).
Another group of proteins that play a role in meiosis are the cohesins. The cohesins form a multimeric complex, which is necessary for sister chromatid cohesion. Such cohesion is used in both meiosis and mitosis, and the cohesions are not meiosis-specific. (The first meiotic division and the end of mitosis both involve the pairing of sister chromatids). However, some of these proteins, Smc3p and a meiosis-specific variant of Sccp1 called Rec8p, are important in forming the axial elements of the synaptonemal complex. These proteins are also used in repair processes, further linking recombination, DNA repair, and meiosis. This linkage appears to be important in pairing in yeast, but it may not be as critical in animals (Haber 1998).
Animals
In nematodes and Drosophila, the pattern appears to be reversed. First, there is a period of loose alignment, wherein "pairing sites" on the chromosomes are matched. The formation of the synaptonemal complex follows shortly thereafter, creating a tight bond between the homologous chromosomes. Only after this synapsis can recombination take place (McKim et al. 1998). Drosophila with mutations in their DNA repair genes can still undergo meiotic synapsis, even though they cannot undergo recombination. Similarly, meiotic synapsis in C. elegans can occur without recombination taking place (Dernberg et al. 1998). Some evidence suggests that synapsis is initiated at regions of heterochromatin (Dernburg et al. 1996), and interactions between the Mei-S332 protein and the heterochromatin around the kinetochore are critical in holding the sister chromatids together (Karpen et al. 1995, 1996; Kerrebrock et al. 1995). The gene for the Mei-S332 protein was discovered by screening mutations for their inability to complete meiosis. In these mutants, sister chromatids separated precociously about 90% of the time.
In mammals, two synaptonemal complex proteins have been characterized. The SCP1 (synaptonemal complex protein 1) protein is a major constituent of the transversal filament. It is thought that SCP1 forms a filamentous dimer whose N terminal ends are located within the central element of the synaptonemal complex, and whose C termini are close to or within the lateral element of the synaptonemal complex (Liu et al. 1996). SCP3 is an important component of the lateral element of the synaptonemtal complex, since male mice homozygous for a loss-of-function knockout mutation in the SCP3 gene are sterile due to massive apoptotic cell death during meiotic prophase. These SCP3-deficient male mice were unable to form axial/lateral elements (Yuan et al. 2000). Therefore, the synaptonemal compexes failed to form, and the chromosomes in the mutant spermatocytes did not synapse. The absence of SCP3 also affected the nuclear distribution of DNA repair and recombination proteins (Rad51 and RPA), as well as SCP1.
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| Figure 1 Mouse spermatocyte nuclei labeled with anti-SCP1 (green), anti-centromere sera (red/yellow), and DNA staining (blue). The upper nucleus is from a wild-type mouse and shows a pachytene spermatocyte that has completed chromosome synapsis. The lower nucleus is from an SCP3-deficient mutant mouse having asynapsed meiotic chromosomes and aberrant and fragmented SCP1 fibers. The zygotene-like meiotic cells seen in the testis of the mutant male mice fail to develop further and instead undergo apoptosis. (After Yuan et al. 2000; permission courtesy of B. Daneholt). |
Another protein found in the synaptonemal complex of mammals is stromalin 3 (Stag3). Stag3 is a homologue of the yeast protein Scc3p that is a subunit of cohesin. Stag3 appears to be involved in chromosome pairing and maintenance of synaptonemal during the pachytene phase of meiosis in a cohesin-like manner (Pezzi 2000). Similarly, the Msh5 protein was found to be important for synaptonemal complex formation, since mice homozygous for a defect in this gene show a meiotic defect, leading to male and female sterility. Cytological examination of prophase I stages in both sexes revealed an extended zygotene stage, characterized by impaired and aberrant chromosome synapsis, that was followed by apoptotic cell death (de Vries et al. 1999; Edelman et al. 1999). Thus, murine Msh5 promotes synapsis of homologous chromosomes in meiotic prophase I.
An important protein has been found that may play a role in meiotic recombination. Moens and colleagues (2000) have found that the helicase whose deficiency leads to Bloom's Syndrome (BS) is needed on human meiotic chromosomes. BS cells have an increased frequency of sister chromatid exchange. Human males homozygous for mutations of the BS helicase not only have immune system problems and susceptibility to cancer; they are also infertile due chromosome abnormalities in their spermatozoa. Antibodies raised against the C terminus of the human Bloom's Syndrome helicase recognize that protein in mouse and human spermatocytes. They are sparsely present on early meiotic prophase chromosomes, but are later found abundantly on synapsed cores, frequently in combination with the recombinases RAD51 and DMC1, and eventually as pure BLM foci. The BLM protein may function in the meiotic recombination process.
It has long been known that synaptonemal complexes appear to reside on the nuclear envelope (Comings and Okada 1971), but the nature of this attachment is not understood nor is its function known. Recent studies (Alsheimer et al. 1999) suggest that that lamin C2, a component of the nuclear envelope that is discontinuously in the nuclear envelope of spermatocytes, attaches to the synaptonemal complex.
It is important to know how these and other proteins interact during human gametogenesis, since most nondisjunction events (such as those leading to trisomies) are thought to be defects of meiotic pairing (see Yoon et al. 1996).
Literature Cited
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Alsheimer, M., von Glasenapp, E., Hock, R., and Benavente, R. 1999. Architecture of the nuclear periphery of rat pachytene spermatocytes: distribution of nuclear envelope proteins in relation to synaptonemal complex attachment sites. Mol. Biol. Cell 10: 1235-1245.
Baker, S. M. and 11 others. 1996. Involvement of the mouse Mlh1 in DNA mismatch repair and meiotic crossing over. Nature Genet. 13: 336-342.
Chua, P. R. and Roeder, G. S. 1998. Zip2, a meiosis-specific protein required for the initiation of chromosome synapsis. Cell 93: 349-359.
Comings, D. E. and Okada, T. A. 1971. Whole mount electron microscopy of human meiotic chromosomes. Exp. Cell Res. 65: 99-103.
de Vries, S. S., Baart, E. B., Dekker, M., Siezen, A., de Rooij, D. G., de Boer, P., te Riele, H. 1999. Mouse MutS-like protein Msh5 is required for proper chromosome synapsis in male and female meiosis. Genes Dev. 13: 523-531.
Dernburg, A. F., Sedat, J. W. and Hawley, R. S. 1996. Direct evidence of a role for heterochromatin in meiotic chromosome segregation. Cell 86: 135-146.
Derburg, A. F., McDonald, K., Moulder, G., Barstead, R., Dresser, M., and Villeneuve, A. M. 1998. Meiotic recombination in C. elegans initiates by a conserved mechanism and is dispensable for homologous chromosome synapsis. Cell 94: 387-398.
Dong, H. and Roeder, G. S. 2000. Organization of the yeast Zip1 protein within the central region of the synaptonemal complex. J Cell Biol. 148: 417- 426.
Edelmann, W., Cohen, P. E., Kneitz, B., Winand, N., Lia, M., Heyer, J., Kolodner, R., Pollard, J. W., and Kucherlapati, R. 1999. Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Nature Genet. 21: 123-127.
Haber, J. E. Searching for a partner. Science 279: 823-824.
Karpen, G. H., Le, M.-H. and Le, H. 1996. Centric heterochromatin and the efficiency of achiasmatic disjunction in Drosophila female meiosis. Science 273: 118-121.
Liu J. G., Yuan, L., Brundell, E., Bjorkroth, B., Daneholt, B., Höög, C.1996. Localization of the N-terminus of SCP1 to the central element of the synaptonemal complex and evidence for direct interactions between the N-termini of SCP1 molecules organized head-to-head. Exp Cell Res. 226: 11-19.
Kerrebrock, A. W., Moore, D. P., Wu, J. S. and Orr-Weaver, T. L. 1995. Mei-S332, a Drosophila protein required for sister-chromatid cohesion, can localize to meiotic centromere regions. Cell 83: 247-256.
McKim K. S., Hayashi-Hagihara A. 1998. Mei-W68 in Drosophila melanogaster encodes a Spo11 homolog: evidence that the mechanism for initiating meiotic recombination is conserved. Genes Dev. 12: 2932-2942.
McKim, K. S., Green-Marroquin, B. L., Sekelsky, J. J., Chin, G., Steinberg, C., Khodosh, R., and Hawley, R.S. 1998. Meiotic synapsis in the absence of recombination. Science 279: 876-878.
Moens, P. B., Freire, R., Tarsounas, M., Spyropoulos, B., and Jackson, S. P. 2000. Expression and nuclear localization of BLM, a chromosome stability protein mutated in Bloom's syndrome, suggest a role in recombination during meiotic prophase. J. Cell Sci. 113: 663-72.
Pezzi, N., Prieto, I., Kremer, L., Perez Jurado, L. A., Valero, C., Del Mazo, J., Martinez, A. C., and Barbero, J. L. 2000. Stag3, a novel gene encoding a protein involved in meiotic chromosome pairing and location of STAG3-related genes flanking the Williams-Beuren syndrome deletion. FASEB J. 14: 581-592.
Yoon, P. W. and eight others. 1996. Advanced maternal age and risk of Down syndrome characterized by the meiotic stage of the chromosomal error: A population-based study. Amer. J. Hum. Genet. 58: 628-633.
Yuan, L., Liu, J. G., Zhao, J., Brundell, E., Daneholt, B.,and Höög C. 2000. The murine SCP3 gene is required for synaptonemal complex assembly, chromosome synapsis, and male fertility. Mol Cell. 5: 73-83.
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