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: 7845984
• 负责人: Susan M Rosenberg
• 金额: $ 76.75万
• 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/7845984
• 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; Nucleotides; Oncogenes; Organism; Proteins; Technology; abstracting; base; interest

DESCRIPTION Abstract An Undiscovered Class of Cancer Genes ABSTRACT 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 id

描述 抽象的 未被发现的癌症基因摘要该项目的中心假设是，存在大量的，高度保存的基因/蛋白质类别，这些基因/蛋白质会调节所有活细胞中自发性DNA损伤的水平，因此，基因组不稳定性的近端，上游效应子/调节剂也是如此。建议这些包括许多高度保守的基本基因，这些基因在人类中有望构成与（上游）不同的两个主要公认类别的“新”类别的癌症基因：基因组核心和守门人基因。但是，由于两个局限性，这些“损伤控制”基因/蛋白质一直未被发现和未被认可。首先，在活细胞中，没有任何技术来分析自发/内源性DNA损伤，尤其是DNA破裂。因此，影响内源性DNA损伤水平的因素主要没有被测定，也没有考虑。其次，许多损伤控制基因可能对生物的生存能力至关重要，而模型生物体中的当前前向遗传学方法（否则可能发现其中一些基因）会偏向基本基因。我们预计损伤控制基因至少包含以下内容：（1）不可避免地会产生与DNA反应的有毒副产物，从而导致碱/核苷酸损伤；（1）正常的代谢途径（碳代谢等）； （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。）所有这些都预计将是非常保守的，因为它们是生命的基础，并且大多数人被期望是必不可少的基因。该项目的目标是 - （1）开发一种新的远期基因组学方法学范式，该范式将允许在生物学上的任何问题中快速识别包括基本基因在内的基因； （2）使用此范式，在简单模型有机体中找到损伤控制基因，确定其在人类中的对应物，然后识别ID