Characterization of posttranscriptional regulatory interactions in response to genotoxic stress

基因毒性应激对生物体来说是一种危及生命的事件，因为它改变了遗传物质的内容和组织。生物体已经开发出多种机制来检测和修复DNA损伤。DNA损伤反应的缺陷和失败可能导致基因组的不稳定和对恶性肿瘤的易感性。在分子水平上了解DNA损伤反应可能为疾病治疗提供新的途径。我们建议系统地剖析DNA损伤反应过程中的转录后调控，涉及DNA损伤的分子组成、结构以及生物学功能。我们打算发现在DNA损伤上显示差异结合的mRNA相互作用蛋白，确定它们的目标转录本，并表征这些蛋白质-RNA相互作用如何影响mRNAs在遗传毒性应激下的命运。我们的结果将有助于将转录后相互作用整合到细胞DNA损伤反应基因调控网络中，并通过识别新的RNA结合蛋白来携带转化医学的潜力，这些蛋白可能调节癌症和神经退行性疾病等病理中的DNA损伤反应。

Genotoxic stress is a life-threatening event for organisms as it alters the content and organization of the genetic material. Organisms have developed multiple mechanisms to detect and repair DNA damage. Defects and failure in DNA damage response may result in genomic instability and predisposition to malignancies. Understanding of DNA-damage responses at the molecular level may provide new avenues for disease management.We propose to systematically dissect posttranscriptional regulation during the response to DNA damage concerning its molecular composition and architecture as well as its biological functions. We intend to discover mRNA-interacting proteins that show differential binding upon DNA damage, to identify their target transcripts and to characterize how these protein-RNA interactions influence the fate of mRNAs in response to genotoxic stress. Our results will be instrumental to integrate posttranscriptional interactions into cellular DNA damage response gene regulatory networks as well as carry the potential for translational medicine by identifying novel RNA-binding proteins, which might modulate DNA damage responses in pathologies such as cancer and neurodegenerative disorders.