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Molecular mechanisms of chromosome organization and recombination control by the meiotic chromosome axis

减数分裂染色体轴染色体组织和重组控制的分子机制

基本信息

批准号：
10387324
负责人：
Kevin Daniel Corbett
金额：
$ 7.63万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-10 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10387324
关键词：
ATP phosphohydrolase Aneuploidy Biochemical Biochemistry Biological Cells Chromatin Loop Chromosome Segregation Chromosome Structures Chromosomes Complex DNA DNA Binding DNA Repair Pathway Diploidy Disease Down Syndrome Environment Eukaryota Excision Family Feedback Filament Foundations Generations Genetic Genetic Recombination Genome Genomic Instability Germ Cells Haploidy Health Homologous Gene Human Human Chromosomes Knowledge Lead Learning Link Live Birth Malignant Neoplasms Mediating Meiosis Meiotic Recombination Molecular Molecular Conformation Molecular Machines Morphology Mus Pathway interactions Ploidies Pregnancy Prophase Proteins Reproduction Role Saccharomyces cerevisiae Sexual Reproduction Source Specificity Spontaneous abortion Structure Testing Turner&apos s Syndrome Work cancer cell cancer type chromosome loss cohesin developmental disease egg homologous recombination member offspring protein complex recruit segregation sperm cell

项目摘要

PROJECT SUMMARY Sexual reproduction in eukaryotes involves the generation of haploid gametes (in humans, sperm and egg cells) in meiosis, followed by the fusion of two gametes to produce diploid offspring. In meiosis, homologous chromosomes recognize one another and become physically linked through a modified homologous recombination DNA repair pathway, and the resulting crossovers enable accurate homolog segregation in the meiosis I division to reduce ploidy. In most eukaryotes including humans, chromosomes are organized as an array of chromatin loops by a highly conserved structure called the chromosome axis. The chromosome axis also recruits and controls DNA cleavage and recombination factors to mediate the formation of crossovers, and is remodeled after crossover formation in a key feedback pathway controlling recombination levels. Here, we propose to combine biochemistry, structure, and genetics in S. cerevisiae and the mouse to determine how the chromosome axis assembles, organizes chromosomes, and mediates crossover formation. We will determine the structures of S. cerevisiae Red1 and mammalian SYCP2:SYCP3, functionally-related chromosome axis “foundation” proteins that we have found share a conserved domain structure and propensity to self-assemble into filaments. We will next determine how these proteins interact with meiotic cohesin complexes, to understand the structural basis for axis-mediated chromosome organization. Next, we will dissect the network of interactions mediated by S. cerevisiae Hop1, a member of the conserved HORMAD family and a master regulator of meiotic recombination, and study how this interaction network changes during meiotic prophase. Hop1’s eventual removal from the chromosome axis, an important feedback pathway controlling recombination levels, is mediated by the AAA+ ATPase Pch2. We will test our hypothesis that Pch2 directly recognizes a specific Hop1 conformation and partially unfolds its HORMA domain to mediate its removal from the axis. Finally, we will examine the structures, DNA binding specificity, and interactions of two meiosis-specific protein complexes, Msh4:Msh5 and Zip2:Zip4:Spo16, to learn how they stabilize specific DNA recombination intermediates and coordinate crossover formation with chromosome axis morphology changes. Overall, the work proposed here will result in a comprehensive molecular picture of how the chromosome axis assembles, coordinates crossover formation, and is then disassembled as recombination proceeds. Understanding the molecular mechanisms of the chromosome axis and associated factors is highly relevant to human health, as errors in meiotic chromosome segregation are a principal cause of miscarriage in humans, and are the source of “aneuploidy disorders” like Down syndrome and Turner syndrome. Moreover, many cancer types show mis-expression of meiotic chromosome axis proteins, including TRIP13, HORMAD1, and SYCP2. A better understanding of these proteins’ mechanisms in their native environment will be critical to determine how their mis-expression might lead to genome instability and cancer.

项目总结

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The molecular basis of monopolin recruitment to the kinetochore.

单极蛋白募集到着丝粒的分子基础。

DOI：
10.1007/s00412-019-00700-0
发表时间：
2019
期刊：
Chromosoma
影响因子：
1.6
作者：
Plowman,Rebecca;Singh,Namit;Tromer,EelcoC;Payan,Angel;Duro,Eris;Spanos,Christos;Rappsilber,Juri;Snel,Berend;Kops,GeertJPL;Corbett,KevinD;Marston,AdeleL
通讯作者：
Marston,AdeleL

A new piece in the kinetochore jigsaw puzzle.

着丝粒拼图中的一个新部分。

DOI：
10.1083/jcb.201407048
发表时间：
2014
期刊：
The Journal of cell biology
影响因子：
0
作者：
Corbett,KevinD;Desai,Arshad
通讯作者：
Desai,Arshad

Dephosphorylation of the Ndc80 Tail Stabilizes Kinetochore-Microtubule Attachments via the Ska Complex.

NDC80尾部的去磷酸化稳定了KineTochore-Microubulule附件，通过SKA络合物。

DOI：
10.1016/j.devcel.2017.04.013
发表时间：
2017-05-22
期刊：
Developmental cell
影响因子：
11.8
作者：
Cheerambathur DK;Prevo B;Hattersley N;Lewellyn L;Corbett KD;Oegema K;Desai A
通讯作者：
Desai A

TRIP13 and APC15 drive mitotic exit by turnover of interphase- and unattached kinetochore-produced MCC.