Function and Regulation of DNA Damage Response Genes

DNA损伤反应基因的功能和调控

基本信息

批准号：
7192534
负责人：
MINGXIA HUANG
金额：
$ 27.74万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-03-01 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7192534
关键词：
Binding Biochemical Biochemistry Biology Cell Cycle Arrest Cell physiology Cells Complex Condition DNA DNA Damage DNA Repair DNA Repair Gene DNA biosynthesis DNA chemical synthesis DNA damage checkpoint DNA-Binding Proteins Deoxyribonucleotides Development Evolution Failure Family Feedback Gene Targeting Genes Genetic Transcription Genomic Instability Genotoxic Stress Homologous Gene Lead Malignant Neoplasms Mediating Methods Modems Molecular Molecular Genetics Numbers Organism Pathway interactions Patients Phosphorylation Phosphotransferases Predisposition Prevention Process Production Proteins Rate Regulation Regulatory Pathway Repression Research Research Personnel Ribonucleotide Reductase Transcriptional Activation Transcriptional Regulation Yeasts base cancer diagnosis cancer therapy cell injury daughter cell derepression gene induction insight programs promoter repaired response transmission process

项目摘要

DESCRIPTION (provided by applicant): The survival of all organisms depends on the faithful transmission of DNA from one cell to its daughter cell. Cells respond to DNA damage by arresting the cell cycle and inducing the transcription of DNA repair genes. The Crt 1 protein has been identified as a key regulator of DNA damage-induced transcription of the genes encoding ribonucleotide reductase (RNR). The broad, long-term objective of this research program is to use modem methods in molecular genetics and biochemistry to understand the mechanisms underlying cellular response to DNA damage. The focus of this project is on the functional studies of Crtl, and to relate this understanding to the regulation of DNA damage response. This proposal also seeks to investigate CRT1-independent mechanism(s) involved in DNA damage-induced transcription. Specific aims of the proposed research are: (1) To characterize the regulation of Crt 1 activities by the upstream checkpoint kinases in order to understand the negative feedback mechanism of the CRTl-mediated DNA damage response. (2) To characterize the interactions between Crtl and the general repressor complex Ssn6/Tup 1 in response to DNA damage in order to understand how the DNA damage checkpoint controls the switch from the repressed state to the induced state. (3) To determine CRTl-independent mechanism(s) involved in the DNA damage-induced transcription of the RNR genes with the ultimate aim of understanding the interplay among different regulatory pathways controlled by the DNA damage checkpoint. Failure of DNA damage response results in genomic instability and cancer predisposition. As a result, this research will contribute to an increased understanding of the complex biology of DNA damage and repair. These studies will also be critical in guiding our efforts to target the DNA damage response process for cancer diagnosis, prevention, and treatment.

描述（由申请人提供）：所有生物体的生存取决于 DNA 从一个细胞到其子细胞的忠实传递。细胞通过阻止细胞周期和诱导 DNA 修复基因的转录来对 DNA 损伤做出反应。 Crt 1 蛋白已被确定为 DNA 损伤诱导的核糖核苷酸还原酶 (RNR) 编码基因转录的关键调节因子。该研究计划的广泛、长期目标是利用分子遗传学和生物化学领域的现代方法来了解细胞对 DNA 损伤反应的机制。该项目的重点是 Crtl 的功能研究，并将这种理解与 DNA 损伤反应的调节联系起来。该提案还旨在研究 DNA 损伤诱导转录中涉及的 CRT1 独立机制。本研究的具体目的是：（1）表征上游检查点激酶对Crt 1活性的调节，以了解CRT1介导的DNA损伤反应的负反馈机制。 (2)表征Crtl与通用阻遏复合物Ssn6/Tup 1之间响应DNA损伤的相互作用，以了解DNA损伤检查点如何控制从阻遏状态到诱导状态的转换。 (3)确定参与DNA损伤诱导的RNR基因转录的CRT1独立机制，最终目的是了解由DNA损伤检查点控制的不同调节途径之间的相互作用。 DNA 损伤反应失败会导致基因组不稳定和癌症易感性。因此，这项研究将有助于加深对 DNA 损伤和修复的复杂生物学的理解。这些研究对于指导我们针对癌症诊断、预防和治疗的 DNA 损伤反应过程的努力也至关重要。