MYC is the most frequently amplified gene in human cancer and is overexpressed as a consequence of mutations in diverse oncogenic signaling pathways. This proposal will address key questions to resolve the mechanism of MYC transcriptional activation, explore the structure of the unique MYC transactivation domain, and study the impact of mRNA cap methylation which may mediate MYC activities as much or more than transcription. Given the central role of MYC in cancer biology, each of these interrelated goals will offer important new insight into the growth of cancer cells and how this may differ from normal cells.
Aim 1 : How does MYC activate transcription? The best characterized MYC cofactor is TRRAP, which links MYC to two large acetyltransferase complexes. We will define the genome wide role of this mechanism in MYC-dependent transcriptional activation and identify the substrate(s) of acetylation. Alternatively, we will explore direct MYC-dependent recruitment of the TFIIH and/or PTEFb kinase complexes which regulate RNA polymerase II initiation and elongation.
Aim 2 : How does MYC enhance mRNA cap methylation? We discovered that MYC can regulate mRNA cap methylation over and above its role in transcriptional activation. This finding has broad ramifications for our understanding of MYC responsive genes since the net effect of increased cap methylation is significantly greater than transcriptional induction for every target gene analyzed. We will use eIF4E-beads to provide a comprehensive assessment of differential cap methylation. We will also define the interactions between MYC, the cap methyltransferase (RNMT) and the RNAPII CTD that are the likely mediators of the activity. Finally, we will explore a broader role for differential cap methylationin other important signaling pathways.
Aim 3 : What is the structure of the unique MYC transactivation domain? The structure of the DNA binding domain was determined many years ago, but little is known about the structure of the MYC transactivation domain, an unanswered question for most transcription factors. We hypothesize that the transactivation domain may acquire a defined structure in complex with a key transcriptional cofactor, TRRAP. The MYC transactivation domain, especially the essential MBII motif, is highly unique and nearly invariant in evolution and could be a target for specific inhibitors of MYC function, in contrast to the heli-loop-helix/leucine-zipper domains that are shared by over 100 other transcription factors.

Public Health Relevance

Cancer is one of the leading causes of death worldwide, and mutations in the gene called c-myc are found in 15-20% of all cancer. Myc functions by binding to DNA and regulating other genes, but how it achieves this remains poorly understood. The goal of this project is to determine which cellular proteins associate tightly with Myc and how these Myc-associated proteins mediate Myc regulatory activity. A better understanding of Myc function will open new avenues for the diagnosis and treatment of cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Dartmouth College
Schools of Medicine
United States
Zip Code
Smits, Nicole C; Kobayashi, Takashi; Srivastava, Pratyaksh K et al. (2017) HS3ST1 genotype regulates antithrombin's inflammomodulatory tone and associates with atherosclerosis. Matrix Biol 63:69-90
Weyburne, Emily S; Wilkins, Owen M; Sha, Zhe et al. (2017) Inhibition of the Proteasome ?2 Site Sensitizes Triple-Negative Breast Cancer Cells to ?5 Inhibitors and Suppresses Nrf1 Activation. Cell Chem Biol 24:218-230
Posternak, Valeriya; Ung, Matthew H; Cheng, Chao et al. (2017) MYC Mediates mRNA Cap Methylation of Canonical Wnt/?-Catenin Signaling Transcripts By Recruiting CDK7 and RNA Methyltransferase. Mol Cancer Res 15:213-224
Posternak, Valeriya; Cole, Michael D (2016) Strategically targeting MYC in cancer. F1000Res 5:
Cowling, V H; Turner, S A; Cole, M D (2014) Burkitt's lymphoma-associated c-Myc mutations converge on a dramatically altered target gene response and implicate Nol5a/Nop56 in oncogenesis. Oncogene 33:3519-27
Cole, Michael D (2014) MYC association with cancer risk and a new model of MYC-mediated repression. Cold Spring Harb Perspect Med 4:a014316
Kaur, Mandeep; Cole, Michael D (2013) MYC acts via the PTEN tumor suppressor to elicit autoregulation and genome-wide gene repression by activation of the Ezh2 methyltransferase. Cancer Res 73:695-705
Doe, Megan R; Ascano, Janice M; Kaur, Mandeep et al. (2012) Myc posttranscriptionally induces HIF1 protein and target gene expression in normal and cancer cells. Cancer Res 72:949-57
Savino, Mauro; Annibali, Daniela; Carucci, Nicoletta et al. (2011) The action mechanism of the Myc inhibitor termed Omomyc may give clues on how to target Myc for cancer therapy. PLoS One 6:e22284
Choi, Seung H; Wright, Jason B; Gerber, Scott A et al. (2010) Myc protein is stabilized by suppression of a novel E3 ligase complex in cancer cells. Genes Dev 24:1236-41

Showing the most recent 10 out of 21 publications