The Influence of Myc on Chromatin and Genome Stability during Carcinogenesis

描述(由申请人提供)：癌症是由于获得了多种基因改变而导致的，这些基因改变产生了持续的增殖和生存优势。虽然由遗传毒性物质引起的DNA损伤通常会引发突变事件，但对癌细胞中损伤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模板过程相协调，影响DNA损伤的获取。具体地说，松弛的染色质是在转录激活过程中诱导的，比浓缩的染色质更容易受到遗传毒性物质的影响。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，将全球染色质结构改变为一种极其宽松的状态。MYC癌蛋白功能在大量癌症中被解除调控，然而它促进癌症发展的确切机制仍然不清楚。具体地说，Myc的解除调控如何影响染色质介导的对遗传毒物的易感性尚不清楚。如果不了解这些机制，我们对癌症促进的理解和预防癌症发生的策略的设计仍然是不完整的。我们的长期研究目标是描绘导致癌症发生的分子决定因素。这个项目的总体目标是表征Myc调节的染色质结构和相应的DNA损伤获取倾向，这有助于获得恶性特征。我们的中心假设是，Myc的解除调控会导致染色质状态的改变，从而增加对DNA损伤的易感性，导致基因组不稳定和肿瘤转化。这些研究的基本原理是，通过证明癌基因可以通过染色质介导的DNA损伤获取机制影响基因组稳定性，它们有可能重塑目前的癌症进化范式。利用创新的方法，我们建议检验我们的中心假设，并通过追求以下特定目标来实现这一应用的研究目标：1)表征Myc功能改变对致癌物易感性的贡献；2)确定与Myc调节的病变获取相关的染色质背景；以及3)确定Myc调节的DNA病变易感性与恶性潜能之间的关系。这项研究有望产生积极的影响，因为它将有助于阐明Myc诱导的基因组不稳定的起源，并提供一种将细胞推向恶性所需的加速突变的机制。预计这项研究的贡献将是确定 MYC调节的机制，调节染色质结构以影响DNA损伤，在转化过程中先于突变事件。这一贡献意义重大，因为它将阐明基因组不稳定的新来源，这是癌细胞发展的先决条件，从而为中断这一过程的治疗机会提供基础。 突变和随之而来的恶变。

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.