Forward Genomics of Damage Control: An Undiscovered Class of Cancer Genes

损伤控制的正向基因组学：一类未被发现的癌症基因

• 批准号: 8316357
• 负责人: Susan M Rosenberg
• 金额: $ 75.98万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8316357
• 关键词: Affect; Animal Model; Biological Assay; Biology; Carbon; Cells; DNA; DNA Damage; DNA biosynthesis; Escherichia coli; Essential Genes; Gatekeeping; Gene Proteins; Genes; Genetic; Genomic Instability; Genomics; Goals; Human; Life; Metabolic Pathway; Metabolism; Mutation; Nucleotides; Oncogenes; Organism; Proteins; Technology; base; interest

The central hypothesis of this project is that there exists a large, highly-conserved class of genes/proteins that regulate levels of spontaneous DNA damage in all living cells, and so are the proximal, upstream effectors/modulators of genome instability. These are proposed to include many highly conserved essential genes that, in humans, are expected to constitute a ¿new¿ class of cancer genes distinct from (upstream of) the two main recognized classes: genomic-caretaker and gatekeeper genes. However these ¿damage-control¿ genes/proteins have remained undiscovered and unrecognized because of two limitations. First, no technology existed to assay spontaneous/endogenous DNA damage, particularly DNA breakage, directly in living cells. Thus, factors that affect the levels of endogenous DNA damage have mostly not been assayed, and not considered. Second, many of the damage-control genes are likely to be essential for organism viability, and current forward-genetic approaches in model organisms, which might otherwise have found some of these genes, are biased against essential genes. We expect the damage-control genes to encompass at least the following: (1) normal metabolic pathways (carbon metabolism, etc.) that unavoidably produce toxic by-products that react with DNA causing base/nucleotide damage; (2) proteins/molecules that scavenge these by-products; (3) DNA replication components. (DNA breaks often result from replication into damage.) All of these are expected to be very highly conserved because they are so basic to life, and most are expected to be essential genes. The goals of this project are--(1) to develop a new methodological paradigm of forward genomics that will allow rapid identification of genes, including essential genes, of interest to any problem in biology; (2) using this paradigm, to find the damage-control genes in the simple model organism E. coli, identify their counterparts in human, then identify and validate the candidate cancer genes in human. The results may form the basis of understanding what is predicted to be a third, very large, highly-conserved and potentially important class of cancerpromoting mutations.

这个项目的中心假设是存在一个大的，高度保守的