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Genetic and environmental factors affecting alternative lengthening of telomeres

影响端粒选择性延长的遗传和环境因素

基本信息

批准号：
10684837
负责人：
Josep M Comeron
金额：
$ 30.62万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684837
关键词：
Affect Aging Air Barrett Esophagus Biological Assay Biological Markers Biology Biosensor Bypass Cadmium Cancer Model Carcinogens Cell Aging Cell model Cells Characteristics Chromosome Structures Chromosomes Computer Models DNA damage checkpoint DNA metabolism Development Disease Early Diagnosis Environmental Exposure Environmental Pollutants Environmental Risk Factor Eukaryota Event Exposure to Frequencies Future Generations Genes Genetic Genetic Recombination Goals Human Individual Intervention Invaded Malignant Neoplasms Mediating Medical Methodology Methods Minority Modeling Molecular Molecular Profiling Molecular Structure Mutation Nature Outcome Oxidative Stress Paraquat Pathology Pathway interactions Population Population Genetics Precancerous Conditions Process Proteins Quantitative Evaluations Regenerative capacity Research Saccharomyces cerevisiae Saccharomycetales Signal Pathway Southern Blotting Structure Survivors System Techniques Telomerase Telomere Maintenance Telomere Pathway Telomere Recombination Telomere Shortening Testing Toxin Ulcerative Colitis Yeast Model System Yeasts age related assault cancer type carcinogenicity diagnostic tool environmental stressor human model innovation insight novel strategies oxidative damage precursor cell prevent senescence stem cells structural determinants telomere

项目摘要

Telomeres protect chromosome ends in eukaryotes. In the absence of telomerase, telomeres shorten, which eventually leads to senescence. A minority of cells, however, can escape senescence and stabilize telomeres by a recombination process called Alternative Lengthening of Telomeres (ALT). ALT is responsible for telomere maintenance in ~15% of cancers, but it also contributes to stabilization of telomeres in aging or stem cells. Thus, understanding the ALT mechanism is important to identify factors that can influence whether and how it occurs. It is also well known that exposure to various environmental stressors and air toxins influence all aspects of telomere biology and promote telomere-related diseases, including various types of cancer. However, the effects of environmental factors on ALT and telomere dynamics are difficult to study, owing to the absence of experi- mental systems to identify and follow the critical steps responsible for ALT establishment in human cells at the molecular level. A key gap in the study of ALT has been, until recently, the lack of quantitative assays. The goal of this research is to unravel the mechanisms of ALT by identifying genetic, structural, and environmental factors affecting ALT. This research takes advantage of a powerful system in yeast, Saccharomyces cerevisiae, where ALT was originally discovered and where ALT can be followed from the beginning of telomere erosion through formation of survivor cells. This research will employ a unique combination of methods that were recently devel- oped by the applicants that enabled a quantitative study of ALT. This research, so far, has yielded three firsts in the field: (i) a population genetics-based assay that determined the frequency of ALT, (ii) ultra-long sequencing described the detailed structure of individual chromosome ends in ALT survivors, and (iii) a combination of com- putational modeling, Southern blot analysis and PacBio sequencing uncovered “molecular milestones” repre- senting different steps of ALT in large populations of yeast cells. Using these new approaches, this research will determine the effects of genetic, chromosome-structural and environmental factors during the steps of ALT, including: (i) the formation of ALT precursor cell populations initiated by eroded chromosome ends; (ii) the de- velopment of ALT survivors taking place in such populations; (iii) the frequency of ALT outcomes, and (iv) the molecular structure of chromosome ends in ALT survivors. This research will test the effect of environmental stressors on ALT, including oxidative damage from paraquat and the effect of cadmium, a ubiquitous environ- mental pollutant and a type I carcinogen. This will provide insight into molecular effects of environmental factors as well as illuminate new molecular mechanisms of ALT formation, potentially uncovering opportunities for med- ical interventions. Furthermore, this research will establish a robust system to evaluate the influence of other environmental contaminants on ALT, and to utilize telomere erosion and ALT formation as a new type of biosen- sor to assess the effects of various genetic changes and environmental assaults on genetic stability. Overall, this study of ALT in yeast is expected to serve as a roadmap to perform quantitative studies of ALT in humans.

在真核生物中，端粒保护染色体末端。在没有端粒酶的情况下，端粒缩短，这最终会导致衰老。然而，少数细胞可以逃脱衰老并稳定端粒。通过一种被称为端粒交替延长(ALT)的重组过程。ALT负责端粒在大约15%的癌症中维持，但它也有助于在衰老或干细胞中稳定端粒。因此，了解ALT机制对于确定可能影响ALT是否发生以及如何发生的因素很重要。众所周知，暴露在各种环境应激源和空气毒素下会影响到端粒生物学和促进端粒相关疾病，包括各种类型的癌症。然而，其影响环境因素对丙氨酸氨基转移酶和端粒动力学的影响因缺乏实验而难以研究。精神系统识别并遵循负责在人类细胞中建立ALT的关键步骤分子水平。直到最近，丙氨酸氨基转移酶研究中的一个关键空白是缺乏定量分析。目标是这项研究的重点是通过识别遗传、结构和环境因素来揭示ALT的机制影响ALT。这项研究利用了酵母中的一个强大的系统，酿酒酵母，其中 ALT最初是被发现的，其中ALT可以从端粒侵蚀开始一直持续到存活细胞的形成。这项研究将采用最近开发的独特方法组合-- 申请者的开放，使ALT的定量研究成为可能。到目前为止，这项研究已经产生了三个第一研究领域：(I)确定ALT频率的基于群体遗传学的分析；(Ii)超长测序描述了ALT幸存者个体染色体末端的详细结构，以及(Iii)COM-2的组合。预测模型、Southern印迹分析和PacBio测序揭示了分子里程碑的代表在大量酵母细胞中发送不同步骤的ALT。使用这些新方法，这项研究将确定在ALT过程中遗传、染色体结构和环境因素的影响，包括：(I)由侵蚀的染色体末端启动的ALT前体细胞群的形成；(Ii) 在这些人群中发生的ALT幸存者的发育；(Iii)ALT结局的频率；以及(Iv)ALT结果染色体的分子结构在ALT幸存者身上结束。这项研究将检验环境的影响对ALT的应激源，包括百草枯的氧化损伤和镉的影响，镉是一种普遍存在的环境物质- 精神污染物和第一类致癌物质。这将提供对环境因素的分子效应的洞察。以及阐明ALT形成的新的分子机制，潜在地揭示了医学- 病理性干预。此外，本研究将建立一个稳健的系统来评估其他因素的影响环境污染物对丙氨酸氨基转移酶的影响，并利用端粒侵蚀和丙氨酸氨基转移酶的形成作为一种新型的生物制剂. 以评估各种遗传变化和环境攻击对遗传稳定性的影响。总的来说，这项对酵母中ALT的研究有望成为对人类ALT进行定量研究的路线图。