Novel mechanism for UVRAG in genome stability and tumor suppression

描述(申请人提供)：由于目前可用的癌症化疗和放射治疗的不可接受的毒性和无效，寻找新的分子靶点的工作正在如火如荼地进行。虽然最初被认为是自噬途径的启动子，但UVRAG(紫外线耐辐射相关基因)现在已经出现在我们最近的研究中，成为基因组真正的守护者。具体地说，我们发现这种蛋白通过靶向DNA-PK来介导受损DNA的修复，并通过靶向CEP63来巡逻中心体的稳定性，而这种方式与其在自噬信号中的作用无关。我们认为UVRAG是一种新的染色体稳定性调节器，支持UVRAG在癌症发展中失活的直接原因。就我们所知，这些研究首次描述了一种与自噬相关的因子，它直接作用于中心体调节和DNA修复，以维持基因组的完整性。因此，这项拟议的研究将扩展这一知识，以全面评估UVRAG与DNA-PK相互作用激活双链断裂(DSB)DNA修复(目标1)和靶向CEP63以防止中心体扩增(目标2)的分子机制，从而维持细胞的结构和数字染色体的完整性。此外，为了确定染色体不稳定和自噬在UVRAG相关肿瘤抑制(目标3)中的体内贡献和特定作用，我们将建立一个药物诱导的转基因小鼠模型，该模型忠实地概括了在人类癌症中发现的UVRAG的致癌损伤。这些目标将使用多学科的创新方法来实现，这些方法集成了最先进的遗传学、生物化学、定量活细胞成像和细胞和小鼠的生理分析，这些细胞和小鼠具有与UVRAG相关的基因的靶向突变，这些基因是调节基因组稳定性和自噬所必需的。这项研究的结果无疑将阐明UVRAG作为自噬肿瘤抑制因子和基因组保护者的新观点，揭示UVRAG、自噬和基因组不稳定性之间的功能相互作用，并为癌症新疗法的发展提供希望。

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.