Role of Deubiquitination in Fanconi Anemia Cancer Susceptibility Pathway

描述(由申请人提供)：已知基因组稳定性途径的遗传或获得性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Fanconi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突变也出现在非FA患者的癌症中，这意味着这些基因在普通人群中参与了肿瘤抑制或基因组维护。这些基因在一个共同的分子途径中作用，调节DNA修复，特别是DNA链间交联链的修复。蛋白质泛素化和去泛素化是参与调节多种细胞途径的动态过程。FA蛋白FANCD2的单素化似乎在DNA损伤的修复中至关重要，因为在FA中突变的许多蛋白质是FANCD2泛素化所必需的。通过对基因家族RNAi文库的筛选，我们发现了一种去泛素化酶，它是FA途径中的一个新成分。尽管最近的许多研究帮助确定了FA途径激活的关键因素，但仍不清楚FA途径的调节是如何实现的。在我的实验室进行的研究旨在了解FA途径中泛素化的正负调节因子之间的微妙平衡。这项拟议的研究涉及控制DNA修复和基因组稳定性的泛素系统的酶。越来越多的证据表明，DNA损伤反应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Fanconi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.