Elucidating Zip1's role in chromosome segregation

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All sexually reproducing organisms use a specialised cell cycle division (meiosis) to generate gametes (e.g. sperm and egg cells in animals, pollen and megaspores in plants, and spores in fungi). During meiosis, a single round of DNA replication is followed by two consecutive nuclear divisions that result in four haploid gametes. The first meiotic division is special in that the equivalent parental ('homologous') chromosomes pair, recombine and eventually segregate away from each other. Crossover recombination is particularly important in many organisms. The physical exchange of DNA and the proteins associated with DNA allow the homologous chromosome pairs to attach to the spindle in a bipolar fashion. Failure of homologous pairs to receive a crossover is associated with inaccurate chromosome numbers in the resulting gametes, leading to chromosomal abnormalities in the offspring such as Down's syndrome and infertility in humans. Since there is variation in the number of crossovers an average cell receives, mechanisms that cope with homologous chromosome pairs without a crossover ('non-exchange' pairs) are important to the genomic integrity of gametes. Some organisms- such as Drosophila- have mechanisms that are capable of ensuring accurate segregation of several non-exchange pairs. In budding yeast, non-exchange pairs do not segregate randomly suggesting that alternative mechanisms for segregation are functioning. Recently, budding yeast was used to model human female infertility, hypothesised to be composed of 'two hits'. The first of these is the failure of a chromosome pair to receive a crossover and the second, is the failure of the spindle checkpoint. Therefore, understanding and identifying factors involved in the accurate segregation of non-exchange pairs ('distributive disjunction') is important. We have identified the first non-spindle checkpoint protein that promotes distributive disjunction in budding yeast. Zip1 aids non-exchange pairs to segregate appropriately at the first meiotic division in the absence of an inhibitor, Msh4. Furthermore, elevated temperature is also required for Zip1 to exert its effect. How Zip1 ensures distributive disjunction is not unknown and we therefore propose several experiments to elucidate and understand how Zip1 acts. For example, does Zip1 help centromeres to stay together thus ensuring that the chromosomes are attached properly to the meiotic spindle? Or does Zip1 play another role, possibly unrelated to any other known role of Zip1? Our experiments combine approaches from molecular biology, microscopy, and genetics to understand how this protein functions.