Two sides of the Myc-induced DNA damage response: from tumor suppression to tumor maintenance

Abstract

Activation of oncogenes is generally associated with the induction of DNA damage response (DDR) signaling, which acts as a barrier to tumor progression. In this review we will present an overview of the DDR associated with oncogenic activation of Myc, with special focus on two opposite and paradoxical aspects of this response: (1) the role of the Myc-induced DDR in tumor suppression; (2) its role in dampening Myc-induced replication stress, thereby protecting the viability of prospective cancer cells. These opposing effects on cancer progression are controlled by two different branches of DDR signaling, respectively ATM/CHK2 and ATR/CHK1. Indeed, while ATM activity constitutes a barrier to malignant transformation, full activation of ATR and CHK1 is essential for tumor maintenance, providing important opportunities for therapeutic intervention. Thus, the Myc-induced DDR acts as a double-edged sword in tumor progression.

Figure 1

Myc induced tumor suppressive pathways. Outline of the p53 dependent pathways involved in Myc induced tumor suppression.

Figure 2

How Myc deals with intrinsic replication stress. Schematic representation of the pathways engaged by Myc to counteract intrinsic replicative stress responses that would limit clonal expansion of (pre)-cancerous cells.

Figure 3

Dual nature of Myc induced DDR. Tumor promoting DDR: Myc engages the replication checkpoint pathway (ATR/CHK1) to allow robust cellular proliferation and avoid cytotoxic DNA damage accumulation. Tumor suppressive DDR: Myc induced DNA damage response triggers tumor suppressive pathways that act as a barrier to malignant transformation.