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Establishment of sister chromatid cohesion

姐妹染色单体凝聚力的建立

基本信息

批准号：
8963972
负责人：
DOUGLAS E KOSHLAND
金额：
$ 50.25万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8963972
关键词：
ATP phosphohydrolase Acetylation Acetyltransferase Address Alleles Amino Acid Sequence Anaphase Architecture Area Binding Biochemical Biological Biological Assay Biological Process Cell Cycle Progression Cell division Cells Chromosome Condensation Chromosome Segregation Chromosome Structures Chromosomes Complex Congenital Abnormality DNA DNA Binding DNA Packaging DNA Repair Defect Diffusion Down-Regulation Drosophila polo protein Ensure Foundations Gene Expression Genetic Germ Cells Grant In Vitro Lead Maintenance Malignant Neoplasms Measures Mediating Modeling Molecular Molecular Models Physical condensation Play Population Process Property Proteins Regulation Regulatory Element Role Saccharomycetales Sister Chromatid Stem cells Testing Transcriptional Regulation base biochemical tools cohesin cohesion crosslink in vitro Assay in vivo inhibitor/antagonist insight molecular modeling novel prevent protein complex public health relevance research study single molecule transmission process

项目摘要

DESCRIPTION (provided by applicant): Smc (structural maintenance of chromosomes) complexes mediate higher-order chromosome structure by tethering together different regions of chromosomes. One Smc complex, cohesin, functions in several DNA processes, including those that require tethers between chromosomes (sister chromatid cohesion and DNA repair) and those that require tethers between two regions in the same chromosome (condensation and transcription regulation). These diverse functions of cohesin are thought to regulate gene expression in stem cells and to prevent errors in chromosome transmission that lead to cancer and birth defects. Cohesin has a remarkable ring architecture resulting from the interactions of four its subunits, Smc1, Smc3, Scc3, and Mcd1 (also known as Scc1/Rad21) (Fig. 1). Cohesin also contains two ATPases associated with the Smc subunits. These remarkable biological and biochemical properties of cohesin inspire the two questions that drive the aims in this proposal: 1) How do cohesin's architecture and ATPase activities mediate its binding to a DNA duplex and enable it to tether two different DNA duplexes? and 2) How is cohesin regulated to ensure that it functions properly in very diverse biological processes? Aim 1 explores the critical but unexplored asymmetric role(s) of the Smc3 and Smc1 ATPases in regulating cohesin binding to chromosomes and chromosome tethering in vivo. Aim 2 characterizes a newly-detected cohesin activity, its oligomerization and its potential to generate tethers. Experiments in this aim will: ) test the role of cohesin oligomerization in cohesion and condensation; 2) interrogate how oligomerization changes during cell cycle progression, is modulated by DNA binding and controlled by cohesin regulators; and 3) identify the amino acid sequences within the Smc subunits that mediate oligomerization. By studying cohesin through the novel roles of the Smc ATPases and cohesin oligomerization, Aims 1 and 2 will elucidate unexplored aspects of cohesin function in vivo. In Aim 3, the molecular basis for cohesin's in vivo activities will be interrogated by in vitro assays to measure cohesin's binding and diffusion along DNA, its oligomerization, its tethering activities, and any structural changes associated with these activities. These analyses will provide the framework to develop a specific molecular model for cohesin's DNA binding and tethering activities. Aim 4 will explore how a newly identified group of regulators parse cohesin function prior to anaphase to ensure the proper maintenance of sister chromatid cohesion and the establishment of condensation. These analyses will provide insights into cohesin's essential functions in chromosome segregation and provide a paradigm for how the activities of Smc complexes are regulated to carry out distinct biological functions. The four aims exploit unusual genetic alleles that trap distinct functional states of cohesin, new cell biological, genetic and biochemical assays for cohesin oligomerization and new population and single molecule assays for assessing cohesin DNA binding and tethering in vitro.

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

ROCC, a conserved region in cohesin's Mcd1 subunit, is essential for the proper regulation of the maintenance of cohesion and establishment of condensation.

DOI：
10.1091/mbc.e14-04-0929
发表时间：
2014-08-15
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Eng T;Guacci V;Koshland D
通讯作者：
Koshland D

Systematic reduction of cohesin differentially affects chromosome segregation, condensation, and DNA repair.

DOI：
10.1016/j.cub.2010.04.018
发表时间：
2010-05-25
期刊：
CURRENT BIOLOGY
影响因子：
9.2
作者：
Heidinger-Pauli, Jill M.;Mert, Ozlem;Davenport, Carol;Guacci, Vincent;Koshland, Douglas
通讯作者：
Koshland, Douglas

Cohesin-independent segregation of sister chromatids in budding yeast.