The Influence of Myc on Chromatin and Genome Stability during Carcinogenesis

描述（由申请人提供）：癌症是由多种基因改变引起的，这种改变产生了持续的增殖和生存优势。虽然基因毒性药物引起的DNA损伤经常引发致突变事件，但对癌细胞中病变获得的决定因素知之甚少。染色质环境是异常动态的，与各种DNA模板化过程协调，影响DNA病变的获得。具体来说，在转录激活过程中诱导的松弛染色质比凝聚染色质更容易受到基因毒性物质的影响。有趣的是，导致基因组不稳定和癌症易感性的Myc转录因子的过度表达，将全球染色质结构改变为一种非常放松的状态。在许多癌症中，Myc癌蛋白的功能是不受调节的，然而它促进癌症发展的确切机制仍然是难以捉摸的。具体来说，Myc解除管制如何影响染色质介导的对遗传毒性药物的易感性尚不清楚。在不了解这种机制的情况下，我们对癌症促进和预防致癌的策略设计的理解仍然不完整。我们的长期研究目标是描述致癌的分子决定因素。该项目的总体目标是表征myc调节的染色质结构和相应的DNA病变获得趋势，这有助于获得恶性特征。我们的中心假设是，Myc去监管化诱导染色质改变状态，从而增加DNA病变获取的易感性，导致基因组不稳定和肿瘤转化。这些研究的基本原理是，通过证明致癌基因可以通过染色质介导的DNA病变获得机制影响基因组稳定性，它们有可能重塑当前癌症进化的范式。利用创新的方法，我们建议通过追求以下具体目标来验证我们的中心假设并实现本应用程序的研究目标：1)表征Myc功能改变对致癌物易感性的贡献；2)确定与myc调控的病变获得相关的染色质背景；3)确定myc调控的DNA病变易感性与恶性潜能的关系。这项研究预计将产生积极的影响，因为它将有助于阐明myc诱导的基因组不稳定性的起源，并提供加速突变所需的机制，以推动细胞向恶性肿瘤发展。本研究的贡献预计是鉴定

DESCRIPTION (provided by applicant): Cancer results from the attainment of multiple genetic alterations, which produce a sustained proliferative and survival advantage. Although DNA lesions induced by genotoxic agents often initiate mutagenic events, little is known about the determinants of lesion acquisition in cancer cells. The chromatin environment, which is exceptionally dynamic in coordination with varied DNA-templated processes, influences the acquisition of DNA lesions. Specifically, relaxed chromatin, which is induced during transcriptional activation, is more vulnerable to genotoxic agents than condensed chromatin. Interestingly, overexpression of the Myc transcription factor, which results in genome instability and cancer predisposition, alters global chromatin structure to a profoundly relaxed state. Myc oncoprotein function is deregulated in a large number of cancers, however the precise mechanism by which it contributes to cancer development remains elusive. Specifically, how Myc deregulation influences chromatin-mediated vulnerability to genotoxic agents is unknown. Without knowledge of such mechanisms, our understanding of cancer promotion and design of strategies to prevent carcinogenesis remain incomplete. Our long-term research goal is to delineate the molecular determinants that contribute carcinogenesis. The overall objective of this project is to characterize Myc-regulated chromatin structure and consequential DNA lesion acquisition tendencies, which aid in the attainment of malignant characteristics. Our central hypothesis is that Myc deregulation induces an altered state chromatin, which increases vulnerability to the acquisition of DNA lesions, leading to genomic instability and neoplastic transformation. The rationale for these investigations is that they have the potential to reshape current paradigms of cancer evolution, by demonstrating that an oncogene can influence genome stability through chromatin-mediated mechanisms of DNA lesion acquisition. Utilizing innovative approaches, we propose to test our central hypothesis and accomplish the research objectives of this application by pursuing the following specific aims: 1) Characterize the contribution of altered Myc function on carcinogen susceptibility; 2) Identify the chromatin context associated with Myc-regulated lesion acquisition; and 3) Determine relationship between Myc-regulated DNA lesion susceptibility and malignant potential. This research is anticipated to have a positive impact because it will assist in elucidating origins of Myc-induced genome instability and provide a mechanism for the accelerated mutagenesis required to propel a cell toward malignancy. The contribution of this research is expected to be the identification of Myc-regulated mechanisms that modulate chromatin structure to influence DNA lesions, which precede mutagenic events during transformation. This contribution is significant because it will illuminate novel origins for genome instability that are prerequisites for the development of a cancer cell, thus providing the foundation for therapeutic opportunities that interrupt the process of mutagenesis and consequent malignant transformation.