Identifying Novel Mechanisms and Regulators of Genome Stability

识别基因组稳定性的新机制和调节因子

• 批准号: 7900823
• 负责人: Karlene A Cimprich
• 金额: $ 7.5万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-02 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900823
• 关键词: Affect; Biological Assay; Candidate Disease Gene; Cell Cycle Arrest; Cell physiology; Cells; DNA; DNA Damage; DNA Repair; DNA biosynthesis; DNA damage checkpoint; DNA lesion; Defect; Development; Diagnosis; Disease; Etiology; Eukaryotic Cell; Event; Failure; Gene Cluster; Genes; Genome; Genome Stability; Genomics; Health; Human; Investigation; Knowledge; Lead; Lesion; Link; Maintenance; Malignant Neoplasms; Mediating; Modeling; Pathway interactions; Phosphotransferases; Physiological Processes; Predisposition; Process; Processed Genes; Proteins; Screening procedure; Series; Signal Pathway; Small Interfering RNA; Source; Syndrome; Testing; Work; environmental agent; genome-wide; human disease; insight; mRNA Precursor; novel; prevent; public health relevance; repaired; research study; response; trait

DESCRIPTION (provided by applicant): The ability of the cell to maintain the stability of its genome is critical for survival, and eukaryotic cells are constantly challenged by both exogenous and endogenous sources of DNA damage. Cells are particularly susceptible to DNA damage during replication, when replication-blocking lesions can lead to collapse of a replication fork and formation of a double-strand break. As a result, cells have finely tuned processes to repair DNA damage during replication and to stabilize and restart forks that have stalled during DNA replication. Importantly, defects in these processes have been linked to a growing number of human diseases, among which are a number of syndromes associated with congenital and developmental defects as well as a predisposition to cancer. The overall objective of the studies proposed here is to identify and characterize new pathways and proteins involved in maintaining genomic integrity and replication fork stability. We recently conducted an unbiased genome-wide siRNA screen in human cells to identify candidate genes involved in these processes. Amongst our screening hits are many genes with no previously known connections to genome stability pathways. Here, we propose a series of additional assays to identify novel effectors of replication fork stability among our candidates. The unbiased approach we have taken has the potential to reveal unexpected connections between genome stability and other cellular processes, and to define new mechanisms by which cells maintain genome stability. Thus, we anticipate that these experiments will open novel avenues of investigation. PUBLIC HEALTH RELEVANCE: Defects in DNA damage response pathways have been linked to a growing number of human diseases, among which are a number of syndromes associated with a predisposition to cancer as well as congenital and developmental defects. Thus, the proteins and processes that we may link to replication fork stability could be responsible for some of these disease, and the knowledge gained from understanding the signaling pathways linked to these syndromes could provide critical insights relevant to their diagnosis, treatment and etiology.

描述（由申请人提供）：细胞维持其基因组稳定性的能力对于生存至关重要，真核细胞不断受到外源和内源 DNA 损伤的挑战。细胞在复制过程中特别容易受到 DNA 损伤，复制阻断损伤可能导致复制叉崩溃并形成双链断裂。因此，细胞可以微调过程来修复复制过程中的 DNA 损伤，并稳定和重新启动 DNA 复制过程中停滞的分叉。重要的是，这些过程中的缺陷与越来越多的人类疾病有关，其中包括许多与先天性和发育缺陷以及癌症易感性相关的综合症。这里提出的研究的总体目标是识别和表征参与维持基因组完整性和复制叉稳定性的新途径和蛋白质。我们最近在人类细胞中进行了无偏倚的全基因组 siRNA 筛选，以确定参与这些过程的候选基因。在我们的筛选结果中，有许多基因与基因组稳定性途径之间没有已知的联系。在这里，我们提出了一系列额外的测定，以鉴定我们的候选者中复制叉稳定性的新效应器。我们采取的公正方法有可能揭示基因组稳定性与其他细胞过程之间意想不到的联系，并定义细胞维持基因组稳定性的新机制。因此，我们预计这些实验将开辟新的研究途径。公共卫生相关性：DNA 损伤反应途径的缺陷与越来越多的人类疾病有关，其中包括许多与癌症易感性以及先天性和发育缺陷相关的综合征。因此，我们可能与复制叉稳定性相关的蛋白质和过程可能是其中一些疾病的原因，并且从了解与这些综合征相关的信号通路中获得的知识可以提供与其诊断、治疗和病因学相关的重要见解。