Novel mechanism for UVRAG in genome stability and tumor suppression

描述（由申请人提供）：由于目前可用的癌症化疗和放疗的不可接受的毒性和无效性，对新分子靶点的研究正在高速进行。虽然最初被鉴定为自噬途径的启动子，但UVRAG（UV辐射抗性相关基因）现在已经在我们最近的研究中成为基因组的真正监护人。具体来说，我们已经发现这种蛋白质通过靶向DNA-PK介导受损DNA的修复，并通过靶向CEP 63以独立于其在自噬信号传导中的作用的方式巡逻中心体稳定性。我们认为UVRAG是一种新的染色体稳定性调节因子，支持UVRAG失活在癌症发展中的直接因果作用。据我们所知，这些研究首次描述了一种自噬相关因子，它直接参与中心体调控和DNA修复，以维持基因组的完整性。因此，拟议的研究将扩展这一知识，以全面评估UVRAG与DNA-PK相互作用的分子机制，以激活双链断裂（DSB）后的DNA修复（Aim 1），并靶向CEP 63以防止中心体扩增（Aim 2），从而保持细胞的结构和数量染色体完整性。此外，为了确定染色体不稳定性和自噬在UVRAG相关肿瘤抑制中的体内贡献和特定作用（目的3），我们将开发药物诱导的转基因小鼠模型，该模型忠实地再现了在人类癌症中发现的UVRAG致癌病变。这些目标将使用多学科的创新方法来解决，这些方法整合了最先进的遗传学，生物化学，定量活细胞成像和细胞和小鼠中的生理学测定，这些细胞和小鼠具有与UVRAG相关的基因中的靶向突变，并需要调节基因组稳定性和自噬。从这项研究中获得的结果无疑将阐明UVRAG作为自噬肿瘤抑制剂和基因组保护剂的新观点，揭示UVRAG，自噬和基因组不稳定性之间的功能相互作用，并为开发新的癌症治疗方法带来希望。

DESCRIPTION (provided by applicant): Due to the unacceptable toxicity and ineffectiveness of currently available cancer chemotherapy and radiation, the search for new molecular targets is in high gear. While initially identified as a promoter of the autophagy pathway, UVRAG (UV irradiation-resistance associated gene) has now emerged in our recent studies as a bona fide guardian of the genome. Specifically, we have discovered that this protein mediates the repair of damaged DNA by targeting DNA-PK and patrols centrosome stability by targeting CEP63 in a manner independent of its role in autophagy signaling. We propose that UVRAG is a novel regulator of chromosomal stability, supporting a direct causal role for UVRAG inactivation in cancer development. To the best of our knowledge, these studies represent the first description of an autophagy-related factor directly functioning in centrosome regulation and DNA repair to maintain genome integrity. Thus, the proposed research will expand on this knowledge to comprehensively assess the molecular mechanisms by which UVRAG interacts with DNA-PK to activate DNA repair upon double-strand breaks (DSBs) (Aim 1) and targets CEP63 to prevent centrosome amplification (Aim 2), thereby maintaining both structural and numeric chromosomal integrity of cells. Furthermore, to determine the in vivo contribution and specific roles of chromosomal instability and autophagy in UVRAG-associated tumor suppression (Aim 3), we will develop a drug-inducible transgenic murine model, which faithfully recapitulates an oncogenic lesion of UVRAG found in human cancers. These aims will be addressed using multidisciplinary innovative approaches that integrate state-of-the art genetic, biochemistry, quantitative live-cell imaging, and physiological assays in cells and in mice with targeted mutations in genes that are related to UVRAG and required for the regulation of genomic stability and autophagy. Results gained from this study will undoubtedly illuminate new views on UVRAG as an autophagic tumor suppressor and a protector of the genome, reveal functional interactions between UVRAG, autophagy, and genomic instability, and also hold promise for the development of novel therapeutics for cancer.