P53-Dependent cell cycle control: response to genotoxic stress

Abstract

p53 protein is involved in key responses to genotoxic stress. These functions underlie the role of p53 as the `guardian of the genome'. In a simplified manner, upon low or repairable levels of DNA damage, p53 mediates the delay or arrest at checkpoints preceding cell replication (the G 1/S checkpoint), and is involved in delaying damaged cells prior premitotic chromosome condensation (the G 2and pre-meiotic check-points) and actual chromosome partition (the spindle check-point). During these delays, an opportunity is given to repair the DNA damage, before its fixation and propagation, that may lead to carcinogenesis. Upon high or irreparable DNA damage, p53 promotes the cells towards apoptosis. Here we review the known molecular pathways by which p53 controls the cell cycle, with a specific focus on the significance of p53-mediated checkpoint response for its `tumor suppressor' function. The data reviewed is concerned with the in vivomouse models including p53 knockout mice, transgenic mice harboring various mutant forms of p53 and mice knocked out for cell-cycle- and apoptosis-asso- ciated genes situated upstream or downstream from p53, that have been elaborated upon over the last few years.