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The modulation of PCNA ubiquitination by p21 and its significance for DNA repair

p21对PCNA泛素化的调节及其对DNA修复的意义

基本信息

批准号：
7172001
负责人：
Carol Prives
金额：
$ 3.94万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7172001
关键词：
Address Affinity Argentina Award Binding Biological Bypass CDKN1A gene Cancerous Cell Cycle Arrest Cell Cycle Regulation Cell Death Cell Survival Cell physiology Cells Cyclin-Dependent Kinase Inhibitor DNA DNA Damage DNA Repair DNA biosynthesis DNA-Directed DNA Polymerase Data Down-Regulation Enzymes Equilibrium Event Genes Genetic Transcription Goals Grant Half-Life Human Impairment In Vitro Institutes Knock-in Mouse Laboratories Link Lysine Mammals Medical Surveillance Melissa Messenger RNA Modification Mono-S Mutation Numbers Outcome PCNA gene Pathway interactions Phase Poly A Polyubiquitin Post-Translational Protein Processing Postdoctoral Fellow Process Protein p53 Proteins Proteolysis Publications Regulation Reporting Repression Research Research Project Grants Role Series Signal Pathway Signal Transduction Slide Stress System TP53 gene Transcriptional Activation Tumor Suppressor Proteins Ubiquitin Ubiquitination Up-Regulation Work Yeasts base cancer therapy career cyclin G mesylate multicatalytic endopeptidase complex mutant novel oncoprotein p21 parent grant pol genes prevent protein degradation protein function protein protein interaction repaired research study response treatment effect ultraviolet irradiation

项目摘要

DESCRIPTION (provided by applicant): While in vitro experiments emphatically demonstrated the inhibitory effect of p21 on PCNA dependent DNA replication and repair it was much harder to arrive to similar conclusions in experiments performed in cells. This might depend, at least in part, on the convergent signals that prevent p21 up-regulation in S phase. We have come across the intriguing observation that a number of genotoxic treatments that induce transient or permanent arrest in S phase coordinately promote p21 down-regulation and PCNA ubiquitination. Moreover, stable p21 expression negatively modulates PCNA ubiquitination, a post-transcriptional modification of the sliding clamp relevant for its DNA re pair-related activities. This observation prompt us to the study of novels aspects of PCNA regulation by p21. We propose to explore the mechanisms for p21 dependent inhibition of PCNA ubqiutination after UV irradiation. This will also facilitate the identification of other molecules that modulate PCNA ubiquitination and are targets of p21. The link between p21 degradation and PCNA ubiquitination will also allow the identification of pathways upstream that coordinate these events. The effects on cell survival of a stable p21 expression during the above mentioned genotoxic treatments might reveal the biological relevance of p21 down-regulation and might be significant for cancer therapy.

描述（由申请人提供）：虽然体外实验着重证明了p21对PCNA依赖性DNA复制和修复的抑制作用，但在细胞中进行的实验中很难得出类似的结论。这可能取决于，至少部分地，在S期的收敛信号，防止p21上调。我们已经发现了一个有趣的观察结果，即一些诱导S期短暂或永久停滞的遗传毒性治疗协同促进p21下调和PCNA泛素化。此外，稳定的p21表达负调节PCNA泛素化，一种与其DNA修复相关活动相关的滑动钳的转录后修饰。这一观察结果促使我们研究p21对PCNA调控的新方面。我们拟探讨p21依赖性抑制紫外线照射后PCNA亚突变的机制。这也将有助于识别其他分子，调节PCNA泛素化，是p21的目标。p21降解和PCNA泛素化之间的联系也将允许识别协调这些事件的上游途径。在上述基因毒性处理期间稳定的p21表达对细胞存活的影响可能揭示p21下调的生物学相关性，并且可能对癌症治疗具有重要意义。