Overview

Regulation of DNA-damage-induced apoptosis is important to oncology in two ways. First, the majority of carcinogens are genotoxins that cause DNA damage and the apoptotic response to carcinogens is an important tumor-suppression mechanism. Second, a number of mainstay cancer therapeutic agents are genotoxins and their efficacies can be influenced by the robustness of DNA-damage-induced apoptosis in tumor cells. This chapter focuses on a network of nuclear factors involved in the transmission of DNA-damage signals to the intrinsic apoptotic machinery. These nuclear factors include DNA-damage sensors, the PIKK-family of protein kinases that these sensors activate, and three downstream nuclear effectors, p53, Abl, and caspase-2 (Figure 39.1). We have chosen to focus on this collection of nuclear factors, which represent only a subset of the DNA-damage signaling pathways, to illustrate two major points: (i) DNA-damage-induced apoptosis is regulated by nuclear proteins that also regulate DNA repair and (ii) DNA damage signals can be independently transmitted by several downstream effectors, i.e. p53, Abl, and caspase-2, to activate intrinsic apoptosis.

DNA damage does not always activate apoptosis

The concept of a linear, hard-wired signaling pathway that links lesions in genomic DNA to the apoptosis machinery would predict that DNA damage should always lead to cell killing, but this is not the case. In cells that undergo DNA-damage-induced apoptosis, death is invariably a delayed response requiring hours of deliberation. Generally speaking, delayed responses to biological perturbations are those that involve the reprogramming of gene expression, which, by nature of the transcription and translation processes, requires time. As the reprogramming of gene expression is under the hierarchical control of a multitude of genetic and epigenetic factors, activation of DNA-damage-induced apoptotic response is highly dependent on the lineage and the developmental stage of a cell. In addition to apoptosis, DNA-damaged cells can choose to undergo premature senescence or adaptation, where cells resume proliferation despite the persistence of DNA lesions. The choice a cell makes among these delayed responses to DNA damage is determined by how a cell reprograms its gene expression.