Role of Deubiquitination in Fanconi Anemia Cancer Susceptibility Pathway

描述（由申请人提供）：已知遗传或获得性基因组稳定性途径的缺陷会导致各种人类病理状况，包括早发性癌症。家族性基因组不稳定或癌症易感性综合征，范可尼贫血（FA），是由至少13个FA基因中的1个突变引起的。其中一些基因的双等位基因突变也发生在非fa患者的癌症中，暗示这些基因在普通人群中抑制肿瘤或维持基因组。这些基因在调节DNA修复的共同分子途径中起作用，特别是DNA链间交联的修复。蛋白质泛素化和去泛素化是一个动态过程，涉及许多细胞途径的调节。FA蛋白FANCD2的单泛素化似乎对DNA损伤的修复至关重要，因为许多FA中突变的蛋白是FANCD2泛素化所必需的。通过筛选基因家族RNAi文库，我们确定了一种去泛素化酶作为FA途径的新组成部分。尽管最近的一些研究已经帮助确定了激活FA通路的关键因素，但仍不清楚FA通路的调节是如何实现的。在我的实验室进行的研究是为了了解FA途径中泛素化的正调控和负调控之间的微妙平衡。本研究主要关注泛素系统中控制DNA修复和基因组稳定性的酶。越来越多的证据表明，DNA损伤反应中的缺陷可能导致癌症的发生。我们的研究结果将有助于确定范可尼贫血途径的分子机制，以及该途径的失调如何导致肿瘤发生。

DESCRIPTION (provided by applicant): Inherited or acquired deficiencies in genome stability pathways are known to cause a variety of human pathological conditions, including early onset cancer. The familial genome instability or cancer susceptibility syndrome, Fanconi Anemia (FA), is caused by mutations in 1 of at least 13 FA genes. Biallelic mutations in some of these genes also occur in cancers of non-FA patients, implicating these genes in tumor suppression or genome maintenance among the general population. These genes act in a common molecular pathway that modulates DNA repair, especially the repair of DNA interstrand cross-links. Protein ubiquitination and deubiquitination are dynamic processes implicated in the regulation of numerous cellular pathways. Monoubiquitination of the FA protein FANCD2 appears to be critical in the repair of DNA damage because many of the proteins that are mutated in FA are required for FANCD2 ubiquitination. By screening a gene family RNAi library, we identified a deubiquitinating enzyme as a novel component of the FA pathway. Despite the number of recent studies that have helped identify key players for the activation of the FA pathway, it is still unclear how the regulation of the FA pathway is achieved. The research conducted in my laboratory is directed towards understanding the delicate balance between the positive and negative regulators of ubiquitination in the FA pathway. The proposed research concerns enzymes of the ubiquitin system controlling DNA repair and genome stability. Accumulating evidence indicates that defects in the DNA damage response can lead to cancer initiation. The results of our studies will help to define the molecular mechanisms of the Fanconi Anemia pathway and how dysregulation of this pathway can lead to oncogenesis.