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.

肿瘤通常是由于体细胞随着时间的推移获得一定数量的体细胞突变，或自发获得特定的染色体易位（CT）而产生的。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个在CT中反复发现。CT通常发生在重要基因中，随后导致驱动不同癌症的强致癌融合蛋白的表达。但是，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？对这种现象的合理解释是“非基因组编码的融合转录物”（NGEFT），它可以在不显示任何遗传畸变的正常人类细胞中发现。我们推测，这些NGEFT可能会导致CT时，他们遇到dsDNA断裂。这些遗传损伤可以由外源性化学物质或内源性过程如细胞凋亡或基因转录诱导。因此，我们希望通过实验证明特定的NGEFT能够诱导染色体易位，此外，证明“基因组RNA”本身在人类细胞中用于修复遗传损伤以保持遗传完整性。这种新的生物过程的机制也将被研究。