Elucidating Zip1's role in chromosome segregation

所有有性生殖的生物体都使用专门的细胞周期分裂（减数分裂）来产生配子（例如动物中的精子和卵细胞，植物中的花粉和大孢子，以及真菌中的孢子）。在减数分裂期间，单轮DNA复制之后是两次连续的核分裂，导致四个单倍体配子。第一次减数分裂是特殊的，因为等价的亲本（“同源”）染色体配对，重组并最终彼此分离。交叉重组在许多生物体中特别重要。DNA和与DNA相关的蛋白质的物理交换允许同源染色体对以双极方式附着在纺锤体上。同源配对未能接受交换与所产生的配子中不准确的染色体数目有关，导致后代的染色体异常，如唐氏综合症和人类不育。由于平均细胞接受的交换数量存在变化，因此科普没有交换的同源染色体对（“非交换”对）的机制对配子的基因组完整性很重要。有些生物，如果蝇，具有能够确保几个非交换对的精确分离的机制。在芽殖酵母中，非交换对不会随机分离，这表明分离的替代机制正在发挥作用。最近，芽殖酵母被用来模拟人类女性不孕症，假设是由“两次打击”。其中第一个是染色体对接收交叉的失败，第二个是纺锤体检查点的失败。因此，理解和识别非交换对的准确分离（“分配分离”）所涉及的因素是重要的。我们已经确定了第一个非纺锤体检查点蛋白，促进芽殖酵母中的分配分离。Zip1有助于非交换对在没有抑制剂Msh4的情况下在第一次减数分裂时适当分离。此外，Zip1发挥其作用还需要升高的温度。Zip1如何确保分配分离并不是未知的，因此我们提出了几个实验来阐明和理解Zip1的作用。例如，Zip1是否帮助着丝粒保持在一起，从而确保染色体正确地附着在减数分裂的纺锤体上？或者Zip1扮演着另一个角色，可能与Zip1的任何其他已知角色无关？我们的实验结合了分子生物学、显微镜和遗传学的联合收割机方法，以了解这种蛋白质的功能。

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.