Cell division

Guardian spirit blesses meiosis

During egg and sperm production, the two copies of a duplicated chromosome must be bound together until it is time for their separation. A protein that protects this chromosomal glue has now been discovered.

It is estimated that about 20% of human eggs have an abnormal number of chromosomes, and it is well known that the incidence of fetuses with three copies of some chromosomes — rather than the usual two — increases markedly with the age of the mother1,2. The fact that human eggs can arrest in the early stages of their creation for up to 45 years is clearly a factor. For this entire period, to prevent abnormal chromosome numbers, the two copies of a duplicated chromosome (‘sister chromatids’) need to remain tethered to each other, and the chromosome needs to be connected to its opposite number, until they are told to separate. On page 510 of this issue, Kitajima et al.3 reveal how the molecular tether between sister chromatids is kept in place.

There are two ways in which cells can multiply: mitosis and meiosis. Mitosis occurs in all the body's tissues, and generates more-or-less identical daughter cells; it serves the purpose of, for example, replacing cells lost through general wear and tear. Meiosis occurs only in reproductive tissue and generates reproductive cells.

The starting point for both mitosis and meiosis is a cell with two copies (homologues) of each chromosome, one from the mother and one from the father. These chromosomes are duplicated, producing homologous pairs of sister chromatids. During mitosis (Fig. 1), the two sister chromatids of each pair are pulled apart to opposite poles of the cell, and the cell splits into two. So, each daughter cell again has two copies of each chromosome.

Figure 1: Mitosis.
figure1

After chromosomes are duplicated, producing pairs of sister chromatids, the chromatids are kept together by a cohesin complex containing the Rad21 protein. When the centromeres attach to the spindle during metaphase, pulling forces generate tension, which activates the separase enzyme. This cleaves Rad21, resulting in the release of cohesion and allowing sister chromatids to move to opposite spindle poles during anaphase.

Meiosis, by contrast, is divided into two stages (Fig. 2). In meiosis I, the two sister chromatids of a pair are held together, and the maternal pair is separated from the paternal pair. In meiosis II, the sister chromatids are finally separated. The result is four cells, each with half the usual number of chromosomes. The cell's genetic complement is restored when it meets a complementary reproductive cell.

Figure 2: Meiosis.
figure2

In meiosis I the centromeres of a pair of sister chromatids work in unison so that they face, and attach to, the same spindle pole. A cohesin complex containing the Rec8 protein holds sister chromatids together at centromeres and along chromosome arms. Anaphase I is triggered by cleavage of arm Rec8 by separase, allowing the homologous pairs to disengage and move to opposite poles. Katajima et al.3 have found that Sgo1 protects Rec8 at centromeres during anaphase I, so that sister chromatids remain tethered. Sgo1 is degraded after anaphase I (telophase I), so that, at metaphase II, centromeric Rec8 is no longer protected from separase. Cleavage of this centromeric Rec8 at anaphase II allows sister chromatids to separate.

During the early stages of meiosis I, the homologous pairs of sister chromatids are held together along their arms; the two sister chromatids of a pair are also glued together at specialized regions called centromeres. This bonding is achieved in part by cohesin, a complex of cohesive proteins. It is well established that cohesion along the arms must be different from cohesion at centromeres, because later in meiosis I (at the onset of so-called anaphase I), arm cohesion is released but centromere cohesion remains intact, allowing homologous pairs to travel to opposite poles4,5. Whatever is responsible for this difference must be lost by anaphase II of meiosis II, when sister chromatids, in turn, separate4.

Chromosome segregation at anaphases I and II involves two regulated bursts of a specific protein-degrading activity, called separase. This cleaves one subunit (Rec8) of cohesin, first at the arms and later at the centromeres5. But why is Rec8 cleaved only at the arms during anaphase I? How is the Rec8 at centromeres maintained? This is the problem that Kitajima et al.3 address, using fission yeast, Schizosaccharomyces pombe, as their organism of choice.

It was known5,6,7 that Rec8 is normally expressed only during meiosis, when it takes over from its mitotic counterpart, Rad21. But when mitotic cells are manipulated, Rec8 can largely replace Rad21 (ref. 6), hinting that the expression of Rec8 is not, by itself, enough to impose the properties of meiosis I on a normal mitotic division. So it was suggested4,5,8 that perhaps the difference is that there is a factor that protects centro-meric Rec8 during meiosis I. For various reasons, a good candidate for this factor was the fruitfly Mei-S332 protein8. But this molecule fell out of favour, mainly because of a lack of apparent counterparts in other organisms.

Kitajima et al.3 reasoned that if a protector exists in the form of a single protein, then it might usually be expressed only during meiosis, and, if forcibly expressed with Rec8 in mitotic cells, it might protect cohesion at centromeres. This would kill the cells, because sister chromatids would be unable to separate efficiently. So the authors screened for genes that were lethal only when expressed with Rec8 in mitotic fission yeast. They isolated one such gene, which is usually expressed only in meiosis, and named its encoded protein Sgo1, short for ‘Sugoshin’ — ‘guardian spirit’ in Japanese.

Katajima et al. found that expressing Sgo1 with Rec8 in mitotic cells allowed Rec8 to persist at mitotic centromeres. Moreover, Sgo1 associates with centromeres in early meiosis and remains there until anaphase I, as expected (Fig .2). Deleting the gene results in normal chromosome segregation in meiosis I but random segregation of sister chromatids in meiosis II, because of premature loss of cohesion at anaphase I (because all Rec8 is now cleaved). The authors further show that Sgo1 and Rec8 associate in the same complex. These data are consistent with a role for Sgo1 in protecting centromeric Rec8 from separase at the onset of anaphase I.

How is Sgo1 recruited to centromeres? Here, too, Kitajima et al. suggest an answer. During both meiosis and mitosis, a ‘checkpoint’ monitors the attachment of centromeres to the spindle — the apparatus that physically separates chromosomes. This checkpoint also monitors the physical tension between sister centromeres. By doing so it ensures that sister chromatids make the correct attachments and achieve the required arrangement on the spindle9. Previous analyses of fission yeast10 had shown that one checkpoint component, Bub1, is required to maintain Rec8 at centromeres after anaphase I.

Kitajima et al. show that Bub1 is, in fact, required to recruit Sgo1 to centromeres, suggesting a connection between the protection of Rec8 and the spindle checkpoint. One possibility is that the lack of tension between sister centromeres in meiosis I — resulting from their enforced attachment to the same spindle pole — activates Bub1, which then recruits Sgo1. Such a signal would have to differ from that normally associated with a lack of inter-centromere tension; otherwise, division would stop9.

Broadening their findings, Kitajima et al. found that fission yeast contains a protein related to Sgo1, which they call Sgo2. This protein is located at centromeres in mitotic cells, and again the association depends on Bub1. Its function is unclear, although deleting it results in viable cells with a higher rate of chromosome loss. In addition, there is a single Sgo protein, Sgo1, in budding yeast, which seems to behave similarly to fission-yeast Sgo1 and Sgo2. The authors also identified proteins with regions of reasonable similarity in multicellular organisms. One of these proteins is the fruitfly Mei-S332 — so it seems that this protein's closely guarded secret is that it protects meiotic cohesion after all.

Our understanding of the role of Sgo1 in meiotic chromosome segregation has been confirmed and extended by three additional studies in both fission11 and budding12,13 yeast. Further insight has been provided into the role of fission yeast Sgo2 that localizes with meiotic centromeres11. It seems to be required in meiosis I to orient the unified sister-centromeres so that they only engage microtubules protruding from the same spindle pole. Thus, cells with Sgo2 deleted exhibit a primary defect in the segregation of chromosomes during meiosis I (ref. 11). The combined meiotic phenotype of cells lacking both Sgo1 and Sgo2 is essentially identical to that described for cells with no Bub1 (ref. 10). This is consistent with Bub1 being required to recruit these important determiners of chromosome behaviour to meiotic centromeres.

Returning to the prevalence of chromosome-segregation defects in ageing human eggs: could one contributing factor be a premature loss of the protective influence of Sgo1 during meiosis I, resulting in aberrant chromosome segregation in meiosis II? Sgo1 itself is usually degraded during anaphase I (ref. 3), but perhaps its levels also decline stochastically with maternal age in humans. This would, however, account only for the proportion of aberrations that are caused by defective meiosis II — and these are few compared with those occurring in meiosis I (refs 1, 2). Nonetheless, the discovery of the Sgo proteins should prompt further investigations that might provide insight into defects caused by aberrant numbers of human chromosomes.

References

  1. 1

    Hassold, T. & Hunt, P. Nature Rev. Genet. 2, 280–291 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Champion, M. & Hawley, R. S. Nature Cell Biol. 4 (Suppl.), s50–s60 (2002).

    Article  Google Scholar 

  3. 3

    Kitajima, T. S., Kawashima, S. A. & Watanabe, Y. Nature 427, 510–517 (2004).

    ADS  CAS  Article  Google Scholar 

  4. 4

    Rieder, C. L. & Cole, R. J. Cell. Sci. 112, 2607–2613 (1999).

    CAS  PubMed  Google Scholar 

  5. 5

    Petroncki, M., Siomos, M. F. & Nasmyth, K. Cell 112, 423–440 (2003).

    Article  Google Scholar 

  6. 6

    Watanabe, Y. & Nurse, P. Nature 400, 461–464 (1999).

    ADS  CAS  Article  Google Scholar 

  7. 7

    Klein, F. et al. Cell 98, 91–103 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Kerrebrock, A. W., Moore, D. P., Wu, J. S. & Orr-Weaver, T. L. Cell 83, 247–256 (2004).

    Article  Google Scholar 

  9. 9

    Musacchio, A. & Hardwick, K. Nature Rev. Mol. Cell Biol. 3, 731–741 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Bernard, P., Maure, J. F. & Javerzat, J.-P. Nature Cell Biol. 3, 522–526 (2001).

    CAS  Article  Google Scholar 

  11. 11

    Rabitsch, K. P. et al. Curr. Biol. (in the press).

  12. 12

    Katis, V., Galova, M., Rabitsch, K. P., Gregan, J. & Nasmyth, K. Curr. Biol. (in the press).

  13. 13

    Marston, A. L., Tham, W.-H., Shah, H. & Amon, A. Science published online doi:10.1126/science.1094220 (2004).

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Allshire, R. Guardian spirit blesses meiosis. Nature 427, 495–497 (2004). https://doi.org/10.1038/427495a

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.