Multimerization of MYC proteins as oncogenic principle

这三个MYC家族癌蛋白是人类肿瘤发生的核心驱动因素。许多癌基因驱动的肿瘤在整个生命周期中依赖于MYC表达的升高，这表明靶向MYC功能具有很高的治疗潜力。这一建议解决了这种依赖背后的生化和生物物理机制这一核心问题。MYC蛋白表现出许多激活转录因子的特征，传统上被认为是致癌的，因为它们维持了肿瘤细胞特有的基因表达模式。然而，尽管进行了几十年的密集工作，关键的MYC靶基因的身份仍然不清楚。事实上，许多最近的发现揭示了MYC蛋白的生化特征，这些特征与这个模型不同，并认为它们具有独立于基因表达的致癌功能。我的实验室已经确定了两个这样的过程：MYC蛋白促进启动子上依赖转录的双链断裂修复，以及它们解决转录-复制冲突。我们还表明，针对这些过程具有很高的治疗潜力。当复制分叉来临时，MYC蛋白通过终止启动子附近的转录来分解TRCs。这是令人惊讶的，因为如上所述，它们可以作为经典的激活蛋白发挥作用。以前的一些观察已经表明，MYC蛋白可以两种状态存在，一种是激活状态，一种是抑制状态。此外，MYC的激活功能需要持续的蛋白酶体周转，这表明当周转受阻时，MYC蛋白在抑制状态下积累。我们现在发现，这两种状态之间的转变对应于MYC蛋白的多聚化和相变。当MYC周转受阻或细胞受到转录压力时，MYC蛋白聚集在多聚体球形结构中，并定位于染色质上的新位置。引人注目的是，这些站点位于停滞的复制叉子附近，球形结构围绕着停滞的复制叉子。复制应力导致球体形成受阻，导致双链断裂。这表明，MYC球在物理上保护了被阻止的复制叉子不受RNA聚合酶的影响。我们认为，在应激条件下，这种球体对复制叉起到重要的保护作用，而多聚体的能力是MYC普遍存在的致癌功能的核心。这项应用旨在了解MYC多聚化的潜在机制，并开发工具，使我们能够确定多聚化和相变是否确实是MYC致癌功能的核心。

The three MYC family oncoproteins are central drivers of human tumorigenesis. Tumors driven by many oncogenes are dependent on elevated MYC expression throughout their lifespan, suggesting that targeting MYC function has high therapeutic potential. This proposal addresses the central question of what biochemical and biophysical mechanisms underlie this dependence. MYC proteins exhibit many features of activating transcription factors and are traditionally considered oncogenic because they maintain the characteristic gene expression patterns of tumor cells. However, despite decades of intensive work, the identity of critical MYC target genes remains unclear. Indeed, many recent discoveries have revealed biochemical features of MYC proteins that are at odds with this model and argue that they have oncogenic functions independent of gene expression. My laboratory has identified two such processes: MYC proteins promote transcription-dependent double-strand break repair at promoters and they resolve transcription-replication conflicts. We have also shown that targeting these processes has high therapeutic potential. MYC proteins resolve TRCs by terminating transcription near promoters when a replication fork approaches. This is surprising because, as mentioned above, they can function as classical activating proteins. A number of previous observations had already indicated that MYC proteins can exist in two states, an activating and a repressive state. Moreover, continuous proteasomal turnover of MYC is required for its activating functions, suggesting that MYC proteins accumulate in a repressive state when turnover is blocked. We have now found that the transition between the two states corresponds to a multimerization and phase transition of MYC proteins. When MYC turnover is blocked or cells are subjected to transcriptional stress, MYC proteins accumulate in multimeric spherical structures and localize to new sites on chromatin. Strikingly, these sites are located near stalled replication forks, and the spherical structures surround the stalled forks. The blockage of sphere formation resulted in double-strand breaks induced by replication stress. This suggests that MYC spheres physically shield blocked replication forks from RNA polymerase. We propose that such spheres exert an important protective function for replication forks under stress conditions and that the ability to multimerize is central to the pervasive oncogenic functions of MYC. This application aims to understand the mechanisms underlying MYC multimerization and to develop tools that allow us to decide whether multimerization and phase transition are indeed central for the oncogenic functions of MYC.