RNA-vermittelte DNA Reparatur als prinzipieller Auslöser rekurrenter Krebserkrankungen

RNA介导的DNA修复是癌症复发的主要触发因素

• 批准号: 353065907
• 负责人: Professor Dr. Rolf Marschalek
• 金额: --
• 依托单位: Institut für Pharmazeutische Biologie
• 依托单位国家: 德国
• 项目类别: Reinhart Koselleck Projects
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/353065907?language=en
• 关键词: RNA; vermittelte; DNA; Reparatur; als

Tumors usually arise because somatic cells aquire a certain number of somatic mutations over time, or aquire spontaneously a specific chromosomal translocation (CT). The database of the Sanger Cancer Institute has identified so far 595 cancer genes, of which 360 are recurrently found in CTs. CTs usually occur in important genes which subsequently lead to the expression of strong oncogenic fusion proteins driving the different cancers. But how can we explain that different patients carry the same chromosomal translocations, like e.g. a BCR-ABL translocation? A rational explanation for this phenomenon is offered by "non-genomically encoded fusion transcripts" (NGEFT) that can be found in normal human cells that do not exhibit any genetic aberration. We postulate that these NGEFTs may cause CTs when they encounter dsDNA breaks. These genetic lesions can be induced by exogenously applied chemicals, or by endogenous processes like apoptosis or gene transcription. Therefore, we want to demonstrate experimentally that specific NGEFT's are able to induce chromosomal translocations, and moreover, demonstrate that "genomic RNA" is per se being used in human cells for the repair of genetic lesions in order to maintain genetic integrity. The mechanism of this novel biological process will be investigated as well.

肿瘤的发生通常是因为体细胞随着时间的推移获得了一定数量的体细胞突变，或者自发地获得了特定的染色体易位(CT)。到目前为止，桑格癌症研究所的数据库已经确定了595个癌症基因，其中360个是在CT中反复发现的。CTS通常发生在重要的基因中，从而导致强致癌融合蛋白的表达，从而驱动不同的癌症。但我们如何解释不同的患者携带相同的染色体易位，例如bcr-abl易位？“非基因组编码融合转录本”(NGEFT)为这一现象提供了合理的解释，这种转录本可以在没有表现出任何遗传异常的正常人类细胞中找到。我们推测，当这些NGEFT遇到dsDNA断裂时，可能会导致CTS。这些遗传损伤可由外源化学物质或内源性过程(如细胞凋亡或基因转录)引起。因此，我们想要通过实验证明特定的NGEFT能够诱导染色体易位，此外，我们还想证明“基因组RNA”本身正在人类细胞中用于修复遗传损伤，以维持遗传完整性。并对这一新的生物过程的机理进行了探讨。