The Influence of Chromatin Structure on Carcinogen Susceptibility

描述（由申请人提供）：癌细胞通过诱变事件进化，促进获得与恶性转化相关的性状。在突变之前获得病变的决定因素包括DNA序列及其染色质环境，其与不同的DNA模板化过程协调时异常动态。致癌物通常会导致这些DNA损伤，但调节致癌物易感性的基因组稳定性因素仍然没有得到表征。如果不了解这些机制，我们对癌症发生的理解和预防癌变的策略设计仍然是不完整的。我们的长期研究目标是描述启动致癌作用的分子决定因素。本项目的总体目标是确定 染色质介导的机制，影响致癌物诱导的DNA损伤的收购，帮助实现恶性特征。我们的中心假设是，破坏影响染色质结构的途径导致癌前细胞对致癌物的易感性。这些研究的基本原理是，通过证明基因组稳定性因素可以通过调节染色质结构来影响致癌物的易感性，它们有可能重塑当前癌症演变的范式。我们计划通过追求以下具体目标来测试我们的中心假设：1）确定调节染色质结构和致癌物易感性的基因组维持因子; 2）表征与致癌物诱导的DNA损伤获得相关的特定染色质特征。这项研究具有创新性，因为它们可能会发现一类新的调节染色质的基因组稳定性调节因子。此外，该提案中的实验方法是创新的，因为它期望建立新的高通量和高分辨率的 测量DNA损伤和染色质结构的方法。本研究预计将产生以下预期结果：全面鉴定调节致癌物诱导病变获得倾向的基因组稳定性途径;描绘这些基因组稳定性因子发挥作用的染色质介导机制;以及与易感基因组位点相关的染色质特征的高分辨率表征。本申请中提出的研究的贡献预计是阐明调节染色质结构以影响癌发生过程中DNA损伤获得的途径。这一贡献是创新和重要的，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，从而为中断诱变过程和随后的恶性转化的治疗机会提供基础。预期从这些研究中出现的新治疗靶点的实例是与病变获得率改变相关的表观遗传靶点。具体而言，可以调节组蛋白修饰和染色质修饰剂的功能以减轻DNA损伤的产生，从而减少致突变结果。

DESCRIPTION (provided by applicant): Cancer cells evolve through mutagenic events that facilitate the attainment of traits associated with malignant transformation. Determinants of lesion acquisition that precede mutation include the DNA sequence and its chromatin environment, which is exceptionally dynamic in coordination with varied DNA-templated processes. Carcinogens often cause these DNA lesions, yet genome stability factors that regulate carcinogen susceptibility remain uncharacterized. Without knowledge of such mechanisms, our understanding of cancer initiation and design of strategies to prevent carcinogenesis remain incomplete. Our long-term research goal is to delineate the molecular determinants that initiate carcinogenesis. The overall objective of this project is to identify the chromatin-mediated mechanisms that influence carcinogen-induced DNA lesion acquisition that aid in the attainment of malignant characteristics. Our central hypothesis is that disruption of pathways that influence chromatin architecture result in carcinogen susceptibility in premalignant cells. The rationale for these investigations is that they have the potential to reshape current paradigms of cancer evolution, by demonstrating that genome stability factors can influence carcinogen susceptibility through modulation of chromatin structure. We plan to test our central hypothesis by pursuing the following specific aims: 1) Identify genome maintenance factors that regulate chromatin structure and carcinogen susceptibility; 2) Characterize the specific chromatin signature associated with carcinogen-induced DNA lesion acquisition. This proposed studies are innovative because they will likely uncover a novel class of genome stability regulators that modulate chromatin. Furthermore, the experimental approach in this proposal is innovative as it expects to establish novel high-throughput and high-resolution methods to measure DNA lesions and chromatin structure. The following expected outcomes are anticipated from this research: comprehensive identification of genome stability pathways that regulate propensities for carcinogen-induced lesion acquisition; the delineation of chromatin-mediated mechanisms by which these genome stability factors function; and high resolution characterization of the chromatin signature that is linked to susceptible genomic loci. The contribution of the research proposed in this application is expected to be the elucidation of pathways that modulate chromatin structure to influence DNA lesion acquisition during carcinogenesis. This contribution is innovative and 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. Examples of new therapeutic targets that are expected to emerge from these studies are epigenetic targets associated with altered rates of lesion acquisition. Specifically, the function of histone modifications and chromatin modifiers could be modulated to mitigate the production of DNA lesions, thereby reducing mutagenic outcomes.