Cell cycle checkpoint signaling through the ATM and ATR kinases (original) (raw)

  1. Robert T. Abraham1
  2. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA

The genomes of eukaryotic cells are under continuous assault by environmental agents (e.g., UV light and reactive chemicals) as well as the byproducts of normal intracellular metabolism (e.g., reactive oxygen intermediates and inaccurately replicated DNA). Whatever the origin, genetic damage threatens cell survival, and, in metazoans, leads to organ failure, immunodeficiency, cancer, and other pathologic sequelae. To ensure that cells pass accurate copies of their genomes on to the next generation, evolution has overlaid the core cell-cycle machinery with a series of surveillance pathways termed cell-cycle checkpoints. The overall function of these checkpoints is to detect damaged or abnormally structured DNA, and to coordinate cell-cycle progression with DNA repair. Typically, cell-cycle checkpoint activation slows or arrests cell-cycle progression, thereby allowing time for appropriate repair mechanisms to correct genetic lesions before they are passed on to the next generation of daughter cells. In certain cell types, such as thymocytes, checkpoint proteins link DNA strand breaks to apoptotic cell death via induction of p53. Hence, loss of either of two biochemically connected checkpoint kinases, ATM or Chk2, paradoxically increases the resistance of immature (CD4+CD8+) T cells to ionizing radiation (IR)-induced apoptosis (Xu and Baltimore 1996; Hirao et al. 2000).

In a broader context, cell-cycle checkpoints can be envisioned as signal transduction pathways that link the pace of key cell-cycle phase transitions to the timely and accurate completion of prior, contingent events. It is important to recognize that checkpoint surveillance functions are not confined solely to the happenings within the nucleus–extranuclear parameters, such as growth factor availability and cell mass accumulation, also govern the pace of the cell cycle (Stocker and Hafen 2000). However, for the purposes of this review we will focus exclusively on the subset of checkpoints that monitor the status and structure of chromosomal DNA …