Two Novel Sir2-Interacting Proteins in Yeast

酵母中两种新型 Sir2 相互作用蛋白

• 批准号: 6847103
• 负责人: RUSSELL P DARST
• 金额: $ 4.83万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6847103
• 关键词: Saccharomyces cerevisiae; amidohydrolases; biological signal transduction; cell age; enzyme activity; functional /structural genomics; fungal genetics; fungal proteins; gene induction /repression; genetic regulation; metabolism; nicotinamide adenine dinucleotide; phenotype; postdoctoral investigator; protein protein interaction; yeast two hybrid system

DESCRIPTION (provided by applicant): Incidence of cancer increases with age. The multiple-hit hypothesis posits that this direct correlation arises from a requirement for multiple genomic mutations before a cell becomes cancerous. In contrast, a direct link has been discovered between aging and genomic instability in the model organism Saccharomyces cerevisiae, a single-celled yeast. The Sir2 protein is limiting for lifespan in yeast, and is important for maintaining genomic integrity. Sir2 enzymatic activity is limited by the abundance of a metabolite called NAD(+), indicating that Sir2 may connect metabolism and aging. A human protein homologous to Sir2, called SIRT1 modulates p53, which is a regulator of cell division and is involved in most types of cancer. This suggests that Sir2 has a conserved role in yeast and human in integrating metabolic signals to regulate genomic stability. A major goal of cancer research is to develop predictive models of cancer risk. By deciphering how Sir2 regulates genomic stability, and how Sir2 is regulated by environmental signals, models may be constructed to predict the influence of dietary and environmental factors on cancer risk. To this end, the proposed research will focus on the characterization of two novel Sir2 interactions in yeast and their biological function.

描述（由申请人提供）： 癌症的发病率随着年龄的增长而增加。多次打击的假设认为，这种直接相关性源于在细胞变为癌之前对多个基因组突变的要求。相比之下，在模型有机体酿酒酵母（一种单细胞酵母）中，已经发现了衰老和基因组不稳定性之间的直接联系。 SIR2蛋白在酵母中的寿命有限，对于维持基因组完整性很重要。 SIR2酶活性受到称为NAD（+）的代谢物的丰度的限制，表明SIR2可以连接代谢和衰老。与SiR2同源的人蛋白（称为SIRT1）调节p53，该p53是细胞分裂的调节剂，参与了大多数类型的癌症。这表明SIR2在整合代谢信号以调节基因组稳定性中具有保守的作用。癌症研究的一个主要目标是开发癌症风险的预测模型。通过破译SIR2如何调节基因组稳定性，以及如何通过环境信号调节SIR2，可以构建模型来预测饮食和环境因素对癌症风险的影响。为此，拟议的研究将集中于酵母中两种新型SIR2相互作用及其生物学功能的表征。