The Influence of Myc on Chromatin and Genome Stability during Carcinogenesis

描述（由申请人提供）：癌症是由多种遗传变异引起的，这些变异产生持续的增殖和生存优势。虽然DNA损伤引起的遗传毒性剂往往会引发致突变事件，鲜为人知的是，在癌细胞病变收购的决定因素。染色质环境，这是非常动态的协调与不同的DNA模板的过程，影响收购的DNA损伤。具体而言，松弛的染色质，这是在转录激活过程中诱导，是更容易受到遗传毒性剂比凝聚的染色质。有趣的是，Myc转录因子的过度表达，导致基因组不稳定和癌症易感性，改变了整体染色质结构，使其处于深度松弛状态。Myc癌蛋白的功能在许多癌症中被解除调节，然而它促进癌症发展的确切机制仍然难以捉摸。具体而言，Myc失调如何影响染色质介导的遗传毒性剂的脆弱性是未知的。如果不了解这些机制，我们对癌症促进的理解和预防致癌的策略设计仍然是不完整的。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描述Myc调控的染色质结构和相应的DNA损伤获得趋势，这有助于获得恶性特征。我们的中心假设是Myc失调诱导染色质状态改变，这增加了DNA损伤获得的脆弱性，导致基因组不稳定和肿瘤转化。这些研究的基本原理是，通过证明癌基因可以通过染色质介导的DNA损伤获得机制影响基因组稳定性，它们有可能重塑当前癌症演变的范式。利用创新的方法，我们提出通过追求以下具体目标来测试我们的中心假设并实现本申请的研究目标：1）表征改变的Myc功能对致癌物易感性的贡献; 2）鉴定与Myc调节的损伤获得相关的染色质背景;以及3）确定Myc调节的DNA损伤易感性与恶性潜能之间的关系。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，并为推动细胞走向恶性肿瘤所需的加速诱变提供机制。这项研究的贡献预计将是确定 Myc调控的机制，调节染色质结构，影响DNA损伤，在转化过程中的诱变事件之前。这一贡献是重要的，因为它将阐明基因组不稳定性的新起源，这是癌细胞发展的先决条件，从而为中断该过程的治疗机会提供基础 突变和随之而来的恶性转化。

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.