MYCN-dependent Transcription Termination and Stress Resilience of Transcription

MYCN依赖性转录终止和转录的应激恢复能力

• 批准号: 438596161
• 负责人: Professor Dr. Martin Eilers
• 金额: --
• 依托单位: Lehrstuhl für Biochemie und Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/438596161?language=en
• 关键词: MYCN; dependent; Transcription; Termination; Stress

MYCN is one of three genes of the MYC family and a driving oncogene in many neuroendocrine tumor entities. It encodes a nuclear protein that displays many features of a transcription factor and binds globally to active promoters and many enhancers. Consistently, a large body of literature documents that MYCN, like its counterpart MYC, can both positively and negatively affect the expression of many genes and potentially enhance global transcription rates. It has been difficult, however, to explain the pervasive role of MYC and MYCN in tumorigenesis in terms of changes in expression of its target genes since both proteins have either no or at best very weak effects on expression of the vast majority of genes with MYC/MYCN-bound promoters. As consequence, no consensus model of oncogenic functions of MYC proteins has emerged.We have recently identified the MYCN interactome and studied its dynamics during the cell cycle; this suggested that MYCN proteins co-ordinate transcription elongation with DNA replication. We also found that MYCN can promote premature transcription termination if RNA Polymerase II (RNAPII) stalls. Our unpublished work identifies EXOSC10, a 3'-5´-RNA exonuclease, as a protein that forms a ternary complex with MYCN and RNAPII and may enable MYCN to promote the restart of stalling RNAPII. We speculate from these findings that MYCN specifically coordinates transcription with DNA replication and double-strand break repair and facilitates clearance of promoters if RNAPII stalls due to transcription-induced torsional stress as well as nucleotide imbalances. We hypothesize that the ability to terminate transcription and clear promoters from stalling RNAPII is central to MYCN-dependent oncogenic transformation since it enhances the stress resilience of transcription in tumor cells. The aim of this grant is to explore the underlying mechanisms and test this hypothesis.

MYCN是MYC家族的三个基因之一，并且是许多神经内分泌肿瘤实体中的驱动癌基因。它编码一种核蛋白，该蛋白显示转录因子的许多特征，并与活性启动子和许多增强子全局结合。一致的是，大量文献证明MYCN与其对应物MYC一样，可以积极和消极地影响许多基因的表达，并可能提高整体转录率。然而，很难解释MYC和MYCN在其靶基因表达变化方面在肿瘤发生中的普遍作用，因为这两种蛋白质对具有MYC/MYCN结合启动子的绝大多数基因的表达没有影响或充其量非常弱。因此，没有共识模型的致癌功能的MYC蛋白已经emerged.We最近确定了MYCN相互作用组，并研究了其在细胞周期中的动力学，这表明MYCN蛋白协调转录延长与DNA复制。我们还发现，如果RNA聚合酶II（RNAPII）停滞，MYCN可以促进过早的转录终止。我们未发表的工作确定了EXOSC 10，一种3 '-5'-RNA核酸外切酶，作为一种与MYCN和RNAPII形成三元复合物的蛋白质，并可能使MYCN能够促进停止RNAPII的重新启动。我们从这些发现推测，MYCN特异性地协调转录与DNA复制和双链断裂修复，并且如果RNAPII由于转录诱导的扭转应力以及核苷酸不平衡而停滞，则促进启动子的清除。我们假设终止转录和清除启动子使RNAPII停滞的能力是MYCN依赖性致癌转化的核心，因为它增强了肿瘤细胞中转录的应激恢复力。这项资助的目的是探索潜在的机制并验证这一假设。