The Influence of Chromatin Structure on Carcinogen Susceptibility

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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.