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Elucidating chromosome structure and function through the lens of SMC complexes and R-loops

通过 SMC 复合物和 R 环的镜头阐明染色体结构和功能

基本信息

批准号：
10612775
负责人：
DOUGLAS E KOSHLAND
金额：
$ 73.14万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2026-04-30
项目状态：
未结题

项目摘要

The study of budding yeast has provided fundamental insights into the cell biological processes of all eukaryotes. Its study has also made critical contributions to the understanding and treatment of human disorders like diabetes, congenital disabilities, and cancer. My laboratory uses budding yeast to interrogate three areas of cell biology, the higher-order structure of chromosomes, the prevention of chromosome damage and rearrangements, and the mitigation of environmental stress. The basic unit of chromosomes is chromatin, which is composed of the DNA and associated proteins. The organization of chromatin into higher-order structures is essential for high fidelity chromosome segregation, the repair of DNA damage, and the regulation of gene expression. The molecular mechanisms that organize chromatin are major mysteries in cell biology. In this proposal, we study chromatin organization through the analysis of cohesin, a member of the SMC (Structural Maintenance of Chromosomes) family of protein complexes. Cohesin contributes to chromosome organization by tethering together different chromatin regions within a chromosome or between chromosomes. Cohesin also translocates along a chromosome to extrude loops. This proposal interrogates the molecular mechanisms underlying cohesin's tethering and loop-extrusion activities, the regulation of these activities, and their impact on chromosome structure and function in living cells. Cells also maintain genome stability by preventing and repairing chromosome damage. Chromosome damage is often caused by errors in the execution of intrinsic cellular processes. Indeed, during transcription, an RNA transcript can erroneously hybridize with homologous double-stranded DNA sequences on the chromosomes to generates an RNA-DNA hybrid and a displaced single-stranded DNA. This unusual structure, called an R-loop, can cause DNA damage and chromosome rearrangements. Here, we present experiments to understand why only a subset of R-loops in a genome cause DNA damage and how this damage leads to the large chromosome rearrangements that are a common feature of cancer cells. Finally, cellular stress also arises from extrinsic environmental changes. Understanding how some organisms survive extreme environmental changes has provided critical technical and conceptual advances in biology. We study the ability of yeast to survive desiccation. We showed that the expression of a small protein and simple sugar in yeast is necessary and sufficient for yeast to survive desiccation. These two factors prevent the aggregation of model proteins and modulate membranes in vitro. Here, we propose to elucidate the remarkable biological functions of these two factors by identifying the specific cellular proteins and membranes that they protected during desiccation. These studies will provide fundamental insights into protein and membrane homeostasis beyond desiccation and may generate potential novel applications for biomedicine and agriculture.

对芽殖酵母的研究为了解所有微生物的细胞生物学过程提供了基本的见解。真核生物它的研究也为人类疾病的理解和治疗做出了重要贡献比如糖尿病、先天性残疾和癌症。我的实验室用芽殖酵母来研究细胞生物学，染色体的高级结构，防止染色体损伤，重组，以及减轻环境压力。染色体的基本单位是染色质，它由DNA和相关蛋白质组成。染色质组织成更高级的结构对于高保真的染色体分离是必不可少的， DNA损伤的修复和基因表达的调节。组织的分子机制染色质是细胞生物学中的主要谜团。在这个建议中，我们通过染色质组织研究，分析粘连蛋白，SMC（染色体结构维持）蛋白家族的成员配合物粘着蛋白通过将不同的染色质区域连接在一起来促进染色体的组织在染色体内或染色体之间。粘着蛋白也可以沿着染色体易位，循环这个建议质疑的分子机制的基础上凝聚的束缚和环挤出活动，这些活动的调节，以及它们对活细胞中染色体结构和功能的影响。细胞还通过防止和修复染色体损伤来维持基因组稳定性。染色体损伤通常是由内在细胞过程执行中的错误引起的。事实上，在转录过程中， RNA转录物可以与DNA上的同源双链DNA序列错误地杂交。染色体以产生RNA-DNA杂交体和置换的单链DNA。这种不寻常的结构，被称为R环，可以导致DNA损伤和染色体重排。在这里，我们提出的实验，理解为什么只有基因组中的一部分R环会导致DNA损伤，以及这种损伤如何导致大的染色体重排是癌细胞的常见特征。最后，细胞压力也来自外部环境的变化。了解一些生物体在极端环境变化中生存提供了关键的技术和概念进步，生物学我们研究酵母在干燥条件下的生存能力。我们发现一种小蛋白的表达酵母中的单糖是酵母在干燥环境中生存所必需的。这两个因素阻止了体外模型蛋白聚集和调节膜。在此，我们建议澄清通过鉴定特异性细胞蛋白和细胞膜，它们在干燥过程中保护了它们。这些研究将为蛋白质和膜稳态超越干燥，并可能产生潜在的新的应用生物医学和农业

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genome-wide Map of R-Loop-Induced Damage Reveals How a Subset of R-Loops Contributes to Genomic Instability.

DOI：
10.1016/j.molcel.2018.06.037
发表时间：
2018-08-16
期刊：
Molecular cell
影响因子：
16
作者：
Costantino L;Koshland D
通讯作者：
Koshland D

A model for Scc2p stimulation of cohesin's ATPase and its inhibition by acetylation of Smc3p.

DOI：
10.1101/gad.350278.122
发表时间：
2023-04-01
期刊：
GENES & DEVELOPMENT
影响因子：
10.5
作者：
Boardman, Kevin;Xiang, Siheng;Chatterjee, Fiona;Mbonu, Udochi;Guacci, Vincent;Koshland, Douglas
通讯作者：
Koshland, Douglas

Back to the Future: Mutant Hunts Are Still the Way To Go.

回到未来：寻找突变体仍然是必由之路。