Elucidating Zip1's role in chromosome segregation

阐明 Zip1 在染色体分离中的作用

• 批准号: BB/E000614/1
• 负责人: Eva Hoffmann
• 金额: $ 31.49万
• 依托单位: University of Sussex
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE000614%2F1
• 关键词: Elucidating; Zip1; role; chromosome; segregation

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.

所有有性繁殖生物都使用特殊的细胞周期分裂(减数分裂)来产生配子(例如，动物的精子和卵细胞，植物的花粉和大孢子，以及真菌的孢子)。在减数分裂过程中，单轮DNA复制之后是两个连续的核分裂，从而产生四个单倍体配子。第一次减数分裂的特殊之处在于，相同的亲本(‘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两极方式附着在纺锤体上。同源配对不能接受交换与产生的配子中不准确的染色体数目有关，从而导致后代的染色体异常，如唐氏综合症和人类不孕不育。由于一个普通细胞接收的交换数目存在差异，因此处理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。一些生物--如果蝇--拥有能够确保准确分离几个非交换对的机制。在萌芽酵母中，非交换对并不是随机分离的，这表明替代的分离机制正在发挥作用。最近，萌芽酵母被用来模拟人类女性不孕不育，假设是由两次命中组成。其中第一个是染色体对无法接受交叉，第二个是纺锤体检查点的故障。因此，了解和识别与非交换对准确分离有关的因素(“分布分离”)是重要的。我们已经鉴定出第一个非纺锤体检查点蛋白，它能促进发芽酵母中的分布分离。在没有抑制剂Msh4的情况下，ZIP1帮助非交换对在第一次减数分裂时适当地分离。此外，ZIP1发挥作用还需要较高的温度。ZIP1如何确保分配析取并不是未知的，因此我们提出了几个实验来阐明和了解ZIP1是如何发挥作用的。例如，ZIP1是否有助于着丝粒保持在一起，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、显微镜和遗传学的方法来了解这种蛋白质的功能。

项目成果

Ipl1/Aurora kinase suppresses S-CDK-driven spindle formation during prophase I to ensure chromosome integrity during meiosis.

• DOI: 10.1371/journal.pone.0083982
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Newnham L;Jordan PW;Carballo JA;Newcombe S;Hoffmann E
• 通讯作者: Hoffmann E