The Role of Thoc1 in Normal Development and Cancer

该应用程序的长期目标是了解Thod基因的正常功能并 评估其作为癌症治疗和预后的分子靶点的潜在适用性。Thod编码了一个 最近被鉴定为进化上保守的TREX的组分的蛋白质（pTclI） 复杂. TREX是一个基因子集的有效转录延伸所必需的，它在物理上 将延伸与RNA加工和核输出的过程结合起来。Thod的酵母直向同源物 不是生存所必需的，但该基因的缺失会导致细胞寿命缩短，生长速率降低， 增加对DNA损伤的敏感性。类似地，耗尽pThod的人癌细胞表现出降低的 生长、活力和对遗传毒性化疗药物的抗性。相反，正常分化的细胞 相对不受pThod损失的影响。正常发育对Thod的生理需求 和癌症还有待于在多细胞生物体中进行体内评估。我们假设癌细胞 是唯一依赖于Thod表达的生长和活力，特别是在存在 DNA损伤。为检验这一假设而提出的一般实验方法是测量 pThod缺失对正常发育和恶性转化的影响 Thod等位基因与乳腺癌的本地小鼠模型。提出了四个具体目标：1）测试 pThod耗竭是否抑制体外恶性转化。2)确定pThod是否 消耗影响正常的乳腺发育。3)确定pThod是否耗竭 抑制体内乳腺癌的发生。4)评估pThod水平是否影响 乳腺癌基因毒性治疗。癌细胞积累遗传和表观遗传改变， 使它们具有不必要的增殖潜力，但也使它们具有独特的脆弱性。因此 可以识别出所需的基因。癌细胞的生存能力，而不是正常细胞。等 合成致死基因相互作用确定了治疗的潜在分子靶点， 对癌细胞具有更高的特异性。成功完成拟议的研究将提供原则证明 陶德是一个分子目标由于pThod是新发现的TREX复合物的组分， 它以一种新的作用机制发挥作用。基于靶向pThod的治疗和诊断是 预期产生新的临床反应，新的联合治疗的机会，和预后 信息可能独立于当前使用的标准。这项研究与以下方面高度相关： 人类健康，因为对癌细胞具有更高特异性的新分子靶向疗法显然 needed.提出的实验将确定pThod是否是一个有前途的发展目标 新的治疗方法和预后测试。

The long-term objectives of this application are to understand the normal function of the Thod gene and to assess its potential suitability as a molecular target for cancer therapy and prognosis. Thod encodes a protein (pThocI) that has recently been identified as a component of the evolutionarily conserved TREX complex. TREX is required for the efficient transcriptional elongation of a subset of genes, and it physically couples elongation to the processes of RNA processing and nuclear export. The yeast orthologue of Thod is not essential for viability, but loss of this gene causes reduced cellular lifespan, reduced growth rate, and increased sensitivity to DNA damage. Similarly, human cancer cells depleted of pThod exhibit reduced growth, viability, and resistance to genotoxic chemotherapeutics. In contrast, normal differentiated cells are relatively unaffected by loss of pThod. The physiological requirements for Thod in normal development and cancer have yet to be assessed in vivo in a multicellular organism. We hypothesize that cancer cells are uniquely dependent on Thod expression for growth and viability, particularly in the presence of DNA damage. The general experimental approach proposed for testing the hypothesis is to measure the effects of pThod loss on normal development and malignant transformation using genetically engineered Thod alleles and autochthonous mouse models of breast cancer. Four specific aims are proposed: 1) Test whether pThod depletion inhibits malignant transformation in vitro. 2) Determine if pThod depletion affects normal mammary gland development. 3) Ascertain whether pThod depletion inhibits breast carcinogenesis in vivo. 4) Assess whether pThod levels influence the response of breast cancer to genotoxic therapy. Cancer cells accumulate genetic and epigenetic alterations that endow them with unwanted proliferative potential, but also burden them with unique vulnerabilities. Thus it is possible to identify genes that are required for. the viability of cancer cells, but not normal cells. Such synthetic lethal genetic interactions identify potential molecular targets for therapy that promise to yield greater specificity for cancer cells. Successful completion of the proposed study will provide proof of principle that Thod is such a molecular target. Since pThod is a component of the newly discovered TREX complex, it functions with a novel mechanism of action. Therapies and diagnostics based on targeting pThod are expected to yield novel clinical responses, opportunities for novel combination therapies, and prognostic information potentially independent of currently used criteria. The proposed research is highly relevant to human health because new molecularly targeted therapies with greater specificity for cancer cells are clearly needed. The experiments proposed will determine whether pThod is a promising target for the development of new therapies and prognostic tests.