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：
7540975
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 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7540975
关键词：
Address Affinity Argentina Award Binding Biological Bypass Cancerous Cell Cycle Arrest Cell Cycle Regulation Cell Death Cell Survival Cell physiology Cells Cyclin-Dependent Kinase Inhibitor 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 Melissa Messenger RNA Mesylates Modification Mono-S Mutation Outcome Pathway interactions Phase 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 Tumor Suppressor Proteins Ubiquitin Ubiquitination Up-Regulation Work Yeasts base cancer therapy career cyclin G multicatalytic endopeptidase complex mutant novel parent grant prevent protein degradation protein function protein protein interaction repaired research study response treatment effect ultraviolet irradiation

项目摘要

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 repair-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.

虽然体外实验强调证明了p21对PCNA依赖性DNA的抑制作用复制和修复很难得出在细胞中进行的实验中得出类似的结论。这至少部分取决于阻止p相位中调节的收敛信号。我们已经遇到了一个有趣的观察，即许多诱导短暂或在S期间永久停止协调促进p21下调和PCNA泛素化。而且，稳定的p21表达对PCNA泛素化进行负调节，这是一种转录后修饰滑动夹与其与DNA维修相关的活性相关。这种观察促使我们对小说进行研究 P21调节PCNA的各个方面。我们建议探索紫外线后p21依赖性抑制p21的机制辐照。这也将促进调节PCNA泛素化的其他分子的识别并且是p21的目标。 p21降解与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。对稳定P21细胞存活的影响上述遗传毒性治疗期间的表达可能揭示了p21的生物学相关性下调，对于癌症治疗可能很重要。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

DNA damage induced Pol eta recruitment takes place independently of the cell cycle phase.

DNA 损伤诱导的 Poleta 招募的发生与细胞周期阶段无关。

DOI：
10.4161/cc.8.20.9836
发表时间：
2009
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
0
作者：
Soria,Gaston;Belluscio,Laura;vanCappellen,WA;Kanaar,Roland;Essers,Jeroen;Gottifredi,Vanesa
通讯作者：
Gottifredi,Vanesa

PCNA-coupled p21 degradation after DNA damage: The exception that confirms the rule?