The Bright and the Dark Sides of DNA Repair in Stem Cells
Figure 3
Cell cycle checkpoint pathways, possible targets in GSC. (a) Once DNA damage is identified with the aid of sensors, the checkpoint transducers ATM and ATR undergo conformational change and/or localisation, resulting in their activation. ATM and ATR activate a series of downstream molecules, including the checkpoint kinases Chk1 and Chk2. The latter inactivate CDC25 phosphatases, culminating in cell cycle arrest. AZD7762 (AstraZeneca) and DBH are specific inhibitors of Chk1 and Chk2 kinases. CP466722 (Pfizer) is a specific inhibitor of ATM (modified from [82] with permission). (b) Targeting GSC may yield durable tumor regression. Glioblastomas are heterogeneous tumours containing CD133-positive GSC among other, more differentiated, CD133-negative cells, including glioblastoma progenitor cells. Following radiation, the bulk glioblastoma responds and the tumour shrinks but CD133-positive cells activate checkpoint controls for DNA repair more strongly than CD133-negative cells, resist radiation and prompt the tumour to regrow. These cells could be targeted with DNA-checkpoint blockers (e.g., AZD7762, CP466722 and DBH) to render them radiosensitive (modified from [83] with permission).
