The Influence of Chromatin Structure on Carcinogen Susceptibility

描述(由申请人提供)：癌细胞通过有助于获得与恶性转化相关的特征的突变事件而进化。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，这与不同的DNA模板化过程相协调是异常动态的。致癌物经常引起这些DNA损伤，但调节致癌物易感性的基因组稳定因素仍未确定。如果不了解这些机制，我们对癌症发生的理解和预防癌症发生的策略的设计仍然不完整。我们的长期研究目标是描绘启动癌症发生的分子决定因素。该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损伤获取，有助于获得恶性特征。我们的中心假设是，影响染色质结构的通路的中断会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，它们有可能重塑目前的癌症进化范式。我们计划通过追求以下具体目标来验证我们的中心假设：1)确定调节染色质结构和致癌物易感性的基因组维持因素；2)表征与致癌物诱导的DNA损伤获取相关的特定染色质特征。这项拟议的研究是创新的，因为他们可能会发现一类调节染色质的新型基因组稳定性调节器。此外，本方案中的实验方法是创新的，因为它希望建立新的高通量和高分辨率 方法检测DNA损伤和染色质结构。这项研究预计会产生以下预期结果：全面鉴定调节致癌物诱导的损伤获取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；以及高分辨率表征与易感基因组座位相关联的染色质特征。这项应用中提出的研究的贡献有望阐明在癌变过程中调节染色质结构以影响DNA损伤获取的途径。这一贡献具有创新性和重大意义，因为它将阐明基因组不稳定的新来源，这些来源是癌细胞发展的先决条件，从而为中断突变过程和随后的恶性转化的治疗机会提供基础。预计从这些研究中出现的新治疗靶点的例子是与病变获得率改变相关的表观遗传靶点。具体地说，组蛋白修饰物和染色质修饰物的功能可以被调节以减少DNA损伤的产生，从而减少突变结果。

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.