DNA REPAIR SIGNALING BY NOVEL POLYUBIQUITIN CHAINS

新型多泛素链的 DNA 修复信号传导

• 批准号: 6864432
• 负责人: Cecile M. Pickart
• 金额: $ 34.34万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6864432
• 关键词: DNA binding protein; DNA damage; DNA repair; affinity chromatography; biological signal transduction; fungal proteins; genetic library; polymers; proliferating cell nuclear antigen; proteasome; protein protein interaction; protein structure function; proteolysis; ubiquitin; yeast two hybrid system; yeasts

DESCRIPTION (provided by applicant): Polyubiquitin (polyUb) chains linked through Ub-K63 act as a non-proteolytic signal in the conserved RAD6 DNA damage tolerance pathway, while chains linked through Ub-K48 play a different role, acting as a signal for proteasome proteolysis. These and other observations suggest that the assembly of Ub into different types of polyUb chains is a mechanism for imparting functional diversity in signaling by ubiquitin. Signaling by K63-1inked polyUb chains in DNA damage tolerance is conserved from yeast to man. But despite recent advances, the molecular function of this novel signal remains poorly understood. The proposed research targets this question through mechanistically focused approaches involving biochemical and molecular genetic methods. The specific goals are 1) to elucidate the specific mechanism of DNA damage signaling by K63-1inked polyUb chains (Aims 1-3) and 2) to discover the principles that underlie linkage-specific chain recognition by a small Ub-binding element that occurs in numerous proteins (the UBA domain; Aim 4). The results of our studies may shed light on the causes of cancer and other diseases promoted by genomic instability. Our findings may also suggest ways to inhibit the RAD6 pathway, which could be clinically beneficial in chemotherapy or radiosensitization. Finally, our molecular exploration of (poly)Ub recognition by UBA domains should help to establish fundamental signal recognition principles and may lead to a better appreciation of diversity and specificity in signaling by ubiquitin.

描述（由申请人提供）： 通过UB-K63连接的多泛素（polyub）链充当保守的RAD6 DNA损伤耐受性途径中的非蛋白水解信号，而通过UB-K48连接的链发挥了不同的作用，起着蛋白酶体蛋白水解的信号。这些和其他观察结果表明，将UB组装成不同类型的多核链是泛素信号传导功能多样性的一种机制。从酵母到人，通过K63-1键键链在DNA损伤耐受性中的信号传导。但是，尽管有最近的进步，但这种新型信号的分子功能仍然很少理解。拟议的研究通过涉及生化和分子遗传学方法的机械集中的方法来针对这个问题。特定目标是1）阐明K63-1键链链（目标1-3）和2）发现DNA损伤信号传导的特定机制，以发现以链接特异性链的识别的原理，该原理是通过许多蛋白质（UBA域; Aim; Aim; Aim 4）中的小型UB结合元件识别。我们的研究结果可能会阐明基因组不稳定性促进的癌症和其他疾病的原因。我们的发现还可能提出抑制RAD6途径的方法，这可能在临床上对化学疗法或放射敏化有益。最后，我们对UBA域对（Poly）UB识别（Poly）UB识别的分子探索应有助于建立基本的信号识别原理，并可能导致对泛素信号传导的多样性和特异性的更好欣赏。