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，这些改变产生了持续的增殖和生存优势。尽管基因毒剂引起的 DNA 损伤常常引发诱变事件，但人们对癌细胞中损伤获得的决定因素知之甚少。染色质环境与各种 DNA 模板过程相协调，异常动态，影响 DNA 损伤的获得。具体来说，在转录激活过程中诱导的松弛染色质比浓缩染色质更容易受到基因毒性剂的影响。有趣的是，Myc 转录因子的过度表达会导致基因组不稳定和癌症易感性，从而将整体染色质结构改变为极度松弛的状态。 Myc 癌蛋白功能在许多癌症中失调，但其促进癌症发展的精确机制仍然难以捉摸。具体来说，Myc 失调如何影响染色质介导的对基因毒性物质的脆弱性尚不清楚。如果不了解这些机制，我们对癌症促进和预防癌变策略的设计的理解仍然不完整。我们的长期研究目标是确定导致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随之而来的 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 失调会诱导染色质状态改变，从而增加 DNA 损伤的脆弱性，从而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的癌症进化范式。我们建议利用创新方法来检验我们的中心假设，并通过追求以下具体目标来实现本申请的研究目标：1）表征Myc功能改变对致癌物易感性的贡献； 2) 识别与Myc调节的病变获得相关的染色质背景； 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，并提供一种加速突变的机制，以推动细胞走向恶性肿瘤。这项研究的贡献预计将是确定 Myc 调节机制可调节染色质结构以影响 DNA 损伤，这些损伤先于转化过程中的诱变事件。这一贡献意义重大，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 诱变和随后的恶性转化。

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.