The Influence of Myc on Chromatin and Genome Stability during Carcinogenesis

Myc 在癌变过程中对染色质和基因组稳定性的影响

• 批准号: 8584839
• 负责人: Ashby J. Morrison
• 金额: $ 20.95万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584839
• 关键词: Carcinogens; Cells; Characteristics; Chromatin; Chromatin Structure; DNA; DNA Sequence; DNA Sequence Rearrangement; DNA lesion; DNA mapping; Data; Development; Environment; Event; Evolution; Exposure to; Foundations; Generations; Genetic Transcription; Genome; Genome Stability; Genomic Instability; Goals; In Vitro; Investigation; Knowledge; Lesion; Link; Malignant - descriptor; Malignant Neoplasms; Measurement; Mediating; Mission; Molecular; Mutagenesis; Mutagens; Mutation; Neoplastic Cell Transformation; Nucleosomes; Oncogene Proteins; Oncogenes; Oncogenic; Outcome; Positioning Attribute; Predisposition; Premalignant Cell; Process; Public Health; Publishing; Relaxation; Research; Resolution; Role; Site; Specific qualifier value; Testing; Therapeutic; Transcriptional Activation; United States National Institutes of Health; base; c-myc Genes; cancer cell; cancer prevention; cancer therapy; carcinogenesis; design; histone modification; in vivo; innovation; mutant; novel; overexpression; prevent; public health relevance; transcription factor; tumor

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.

描述（由申请人提供）：癌症是由于实现多种遗传改变而产生的，从而产生持续的增殖和生存优势。尽管遗传毒性剂诱导的DNA病变经常引发诱变事件，但对癌细胞中病变采集的决定因素知之甚少。染色质环境在与不同的DNA模拟过程的协调方面具有异常动态，从而影响了DNA病变的获取。具体而言，在转录激活期间诱导的松弛染色质比凝结染色质更容易受到遗传毒性剂的影响。有趣的是，MYC转录因子的过表达导致基因组不稳定性和癌症的易感性，将整体染色质结构变为深度放松的状态。 MYC癌蛋白功能在大量癌症中被放松，但是它有助于癌症发育的确切机制仍然难以捉摸。具体而言，MYC放松管制如何影响染色质介导的遗传毒性剂的脆弱性尚不清楚。在不了解这种机制的情况下，我们对促进癌症的理解和防止致癌策略的设计仍然不完整。我们的长期研究目标是描述造成致癌作用的分子决定因素。该项目的总体目的是表征MYC调节的染色质结构和结果性DNA病变倾向，这有助于实现恶性特征。我们的中心假设是MYC放松管制会诱导状态染色质的改变，这增加了对DNA病变获得的脆弱性，从而导致基因组不稳定性和肿瘤转化。这些研究的基本原理是，它们有可能通过证明致癌基因可以通过DNA病变的染色质介导的机制来影响基因组稳定性来重塑癌症进化的当前范例。利用创新的方法，我们建议通过追求以下特定目的来检验我们的中心假设并实现本应用的研究目标：1）表征MYC功能对致癌物敏感性的改变的贡献； 2）确定与MYC调节的病变获取相关的染色质环境； 3）确定MYC调节的DNA病变易感性和恶性潜力之间的关系。预计这项研究会产生积极的影响，因为它将有助于阐明MYC诱导的基因组不稳定性的起源，并为将细胞推向恶性肿瘤所需的加速诱变提供了一种机制。这项研究的贡献有望是确定 MYC调节的机制调节染色质结构以影响DNA病变，该病变在转化过程中诱变事件之前。这项贡献很重要，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，从而为中断过程的机会提供了基础 诱变和随之而来的恶性转化。