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.
The proposed research is relevant to public health because it will assist in elucidating the origins of genome instability in precancerous cells and illuminate mechanisms that promote accelerated mutagenesis needed to promote cancer development. The project is relevant to the mission of the NIH because it has the potential to provide a milestone in our understanding of carcinogenesis and open new avenues in the design of strategies to prevent cancer.