To go or not to go?

Abstract

Stem cells have a high and constitutive endogenous activity of the DNA damage response (DDR) pathway1 which may differ in some aspects from the function of the DDR pathway in somatic cells. It is likely that such stemness-related functions of the DDR pathway may play a role in the resistance to genotoxic insult seen in stem cells and cancer cells.2 Lately, it has become clear that the context of the DDR pathway is more complex than first anticipated, and as many other signaling pathways it plays roles beyond its first recognized function as guardian of the genome. One example is the finding that the DDR pathway axis ATR-Chk1 plays a critical function in undamaged cells during mitosis.3 An additional function for H2AX in the DDR pathway, was provided by Andang et al,1 who showed that it mediates proliferation control in stem cells under non-genome damaging conditions. In recent publications by the Hallbook research group, another unexpected function of components of the DDR pathway was reported, again unrelated to direct genome protection. The Hallbook group previously showed that Chk1 in the DDR signaling axis controls the last mitosis in cells undergoing interkinetic nuclear migration (INM) in the developing eye neuroepithelium.4 However, not all cells undergo INM in the neuroepithelium, and the group has now in a carefully executed study, continued to show that Lim1+ horizontal progenitor cells (HPCs), that undergo their last mitosis on the basal side of the retina without INM, have a significantly attenuated dependence on the DDR pathway (Fig. 1).5 Figure 1. Schematic of signaling pathways involving the DNA damage response (DDR) pathway in apical and basal cells in the developing neuroepithelium. Only apical cells undergo interkinetic nuclear migration (INM) and are cell cycle arrested by an activated DDR ... Interestingly, during activation of the ATR-Chk1 (DDR pathway) axis in the developing retinal progenitor cells by Cisplatin, an inducer of ATR/p53 signaling,6 the apical cells were cell cycle arrested as expected, while the basal HPCs cells were not.5 The HPCs nevertheless had a functional p53/p21 pathway regulating cell cycle and apoptosis indicating an inability of the activated DDR pathway to engage the p53 pathway and ultimately apoptosis. However, despite the lack of cell cycle arrest and apoptosis in response to Cisplatin, the DDR pathway was induced and HPCs had elevated γH2AX levels indicating a robust induction of a DDR pathway response. This situation, which has previously been reported in other stem cells1 and in cancer pre-lesions,7 suggests an ability of the HPCs to withstand genotoxic insult and maintain proliferation. Such ability may be a factor that under for example environmental challenging conditions, allows for accumulation of mutations that later may drive development of cancer initiating cells. On the other hand, critical progenitor cell types may maintain capacity to divide and generate new cells during developmental or repair processes – a last resort for survival when most other more sensitive cells are lost to apoptosis. The attenuated DDR pathway response is then a trade off between immediate survival and risking cancer at a later time.