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.

该项目的中心假设是，存在大量的，高度保存的类 调节所有活细胞中赞助DNA损伤水平的基因/蛋白质，因此 基因组不稳定性的近端，上游效应/调节剂。这些被提议 包括许多高度构成的基本基因，在人类中，预计将构成一个 新的癌症基因与（上游）不同的两个主要公认类别不同： 基因组核心和守门基因。但是这些»损伤控制基因/蛋白质 由于有两个局限性，未被发现和未被发现。首先，没有技术 存在直接在 活细胞。那就是影响内源性DNA损伤水平的因素主要不是 被分配了，不考虑。其次，许多损伤控制基因可能是 对于生物的生存能力和模型生物中的当前前向遗传学方法至关重要， 否则可能发现其中一些基因会偏向基本基因。 我们期望损伤控制基因至少包含以下内容：（1）正常代谢 途径（碳代谢等）不可避免地会产生与 DNA导致碱/核苷酸损伤； （2）清除这些副产品的蛋白质/分子； （3）DNA复制成分。 （DNA断裂通常是由于复制造成损害而导致的。） 这些预计将是非常保守的，因为它们是如此基础，大多数是 预计将是必不可少的基因。 该项目的目标是 - （1）开发一个新的方法学范式 将允许快速鉴定在内的基因，包括基本基因，感兴趣的基因组学 生物学上的任何问题； （2）使用此范式，在简单中找到损伤控制基因 模型有机体大肠杆菌，识别人类中的对应物，然后识别并验证 人类中的候选癌基因。结果可能构成理解什么是 预计将是三分之一的，非常大的，高度保守的，潜在的癌症促进性类别 突变。