Abstract
MYC is a transcription factor that controls the expression of a large fraction of cellular genes linked to cell cycle progression, metabolism and differentiation. MYC deregulation in tumors leads to its pervasive genome-wide binding of both promoters and distal regulatory regions, associated with selective transcriptional control of a large fraction of cellular genes. This pairs with alterations of cell cycle control which drive anticipated S-phase entry and reshape the DNA-replication landscape. Under these circumstances, the fine tuning of DNA replication and transcription becomes critical and may pose an intrinsic liability in MYC-overexpressing cancer cells. Here, we will review the current understanding of how MYC controls DNA and RNA synthesis, discuss evidence of replicative and transcriptional stress induced by MYC and summarize preclinical data supporting the therapeutic potential of triggering replicative stress in MYC-driven tumors.
Highlights
MYC is a transcription factor that controls the expression of a large fraction of cellular genes linked to cell cycle progression, metabolism and differentiation
MYC Is a Transcription Factor and Oncogene c-MYC ( MYC), which is a transcription factor belonging to the basic helixloop-helix–leucine zipper family, requires dimerization with its obligatory partner MAX in order to regulate transcription
MYC is part of the immediate-early gene program, its expression being controlled by cytokines and growth factor signaling, where it regulates the transcription of genes required for cell division, cell growth and cellular metabolism [4]
Summary
MYC controls the transcription of a large number of protein-coding genes and noncoding RNAs, being both an activator or a repressor, depending on the specific target. MYC levels are raised due to either genetic events or oncogenic signaling, MYC will bind an increasing number of promoters and enhancers, and depending on the level of expression, may reach a stage at which it binds all accessible regulatory regions (a phenomenon dubbed as MYC invasion) [11,12,13,14]. In these extreme cases, the number of MYC-regulated genes can rise dramatically; yet, both binding affinity and efficiency of transactivation will still be modulated by the presence of E-boxes (i.e., sequence-specific gene regulation) [11,13].
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