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Complex Genomic Rearrangements by BIR and mmBIR

BIR 和 mmBIR 进行复杂基因组重排

基本信息

批准号：
9377246
负责人：
Anne Marie Casper
金额：
$ 44.1万
依托单位：
EASTERN MICHIGAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

项目摘要

Chromosomal rearrangements in tumor genomes and in disease-causing copy number variations (CNVs) are often highly complex. It has been suggested that these rearrangements in human cells result from repair pathways that are engaged when DNA replication forks stall or collapse. The repair pathways hypothesized to be involved are break-induced replication (classical BIR) and the error-prone microhomology-mediated break- induced replication (mmBIR) mechanism. It remains unclear what conditions prompt repair by mmBIR rather than the (relatively) conservative BIR pathway, and much remains to be understood about how mmBIR generates complex rearrangements. The aims of this proposal build on our previous work studying BIR in yeast. We will use the powerful genetic tools of the yeast model system to further compare and characterize these two repair pathways. In the first aim of this proposal, we will characterize conditions that promote mmBIR. We will study whether mmBIR can occur under “typical” cellular conditions, and whether it is employed more frequently under conditions of oxidative stress, which are known to lower the level of key proteins needed for classical BIR. We will also study whether processing of the broken end influences engagement of the mmBIR repair pathway. In the second aim, we will characterize template choice in the mmBIR pathway to determine how much homology is required and whether mmBIR is constrained by physical distances between templates involved. The experiments in both of these aims will test hypotheses about the models of mmBIR and will help us understand which situations and environments promote mmBIR-mediated complex genomic rearrangements in tumors and CNVs.

肿瘤基因组和致病拷贝数变异（CNVs）中的染色体重排往往是非常复杂的。有人认为，人类细胞中的这些重排是由修复引起的。当DNA复制叉停滞或崩溃时，参与的途径。假设修复途径涉及的是断裂诱导的复制（经典BIR）和易错微同源介导的断裂- 诱导复制（mmBIR）机制。目前还不清楚是什么情况促使mmBIR修复，比（相对）保守的BIR途径，还有很多关于mmBIR如何产生复杂的重排。这项建议的目的是建立在我们以前研究BIR的工作基础上，酵母我们将使用酵母模型系统的强大遗传工具来进一步比较和表征这两种修复途径。在本提案的第一个目标中，我们将描述促进 mmBIR。我们将研究mmBIR是否可以在“典型”细胞条件下发生，以及它是否是在氧化应激的条件下更频繁地使用，这是已知的降低关键水平，经典BIR所需的蛋白质。我们还将研究处理断头是否会影响参与mmBIR修复途径。在第二个目标中，我们将描述模板选择在 mmBIR途径，以确定需要多少同源性以及mmBIR是否受到物理限制。模板之间的距离。这两个目标的实验都将检验关于 mmBIR的模型，并将帮助我们了解哪些情况和环境促进mmBIR介导的复杂的基因组重排。