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

描述 摘要 一个未被发现的癌症基因的类别摘要该项目的中心假设是，存在一个大的，高度保守的基因/蛋白质类，调节所有活细胞中自发DNA损伤的水平，因此是近端，上游效应器/基因组不稳定性的调节剂。这些被提议包括许多高度保守的必需基因，在人类中，这些基因被期望构成与两个主要的公认类别（基因组看守基因和看门基因）（上游）不同的“新”类别的癌症基因。然而，由于两个限制，这些“损伤控制”基因/蛋白仍然未被发现和未被识别。首先，没有技术可以直接在活细胞中测定自发/内源性DNA损伤，特别是DNA断裂。因此，影响内源性DNA损伤水平的因素大多没有被测定，也没有被考虑。第二，许多损伤控制基因可能是生物体生存所必需的，而目前在模式生物中的正向遗传方法可能已经发现了这些基因中的一些，对必需基因有偏见。我们预计损伤控制基因至少包括以下几个方面：（1）正常代谢途径（碳代谢等）;其不可避免地产生与DNA反应导致碱基/核苷酸损伤的有毒副产物;（2）抑制这些副产物的蛋白质/分子;（3）DNA复制组分。(DNA断裂通常是由复制造成的。所有这些基因都是高度保守的，因为它们是生命的基础，而且大多数都是必需基因。本项目的目标是：（1）发展一种新的正向基因组学的方法学范式，可以快速鉴定生物学中任何问题所感兴趣的基因，包括必需基因;（2）利用这种范式，在简单的模式生物E.大肠杆菌，鉴定它们在人体中的对应物，

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