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中的遗传性或获得性缺陷会导致多种人类病理状况，包括早发性癌症。家族性基因组不稳定性或癌症易感性综合征，范可尼贫血（FA），是由至少13个FA基因中的一个突变引起的。这些基因中的一些的双等位基因突变也发生在非FA患者的癌症中，暗示这些基因在一般人群中的肿瘤抑制或基因组维持中。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涉及许多细胞途径调节的动态过程。FA蛋白FANCD 2的单泛素化似乎在DNA损伤的修复中是至关重要的，因为FA中突变的许多蛋白质是FANCD 2泛素化所必需的。通过筛选基因家族RNAi文库，我们鉴定了一种去泛素化酶作为FA途径的新组分。尽管最近的一些研究已经帮助确定了FA通路激活的关键参与者，但仍然不清楚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途径中泛素化的正负调节剂之间的微妙平衡。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范可尼贫血通路的分子机制，以及该通路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.