MYC-Induced Replicative Stress: A Double-Edged Sword for Cancer Development and Treatment

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.

Keywords: DNA replication; MYC; cancer therapy; replicative stress; transcription; transcription stress.

Figure 1

Processes and factors that contribute to MYC-induced hyper-transcription and are needed to prevent transcriptional stress.

Figure 2

Schematic view of the most common mechanisms leading to replicative stress. Arrows are pointing to those events that are controlled by MYC and that can either support DNA replication or can predispose cells to replicative stress. Text boxes: details for the processes and the factors implicated in MYC-induced replicative stress.

Figure 3

Overview of potential sources of MYC-induced replicative stress (on the left) and of processes that render replication stress latent in MYC-overexpressing cells (on the right). As argued in the text, these processes represent an attractive liability of MYC-driven cancers that could be exploited therapeutically.