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The genomes of eukaryotic cells are under continuous assault by environmental agents (e. g., UV light and re-active chemicals) as well as the byproducts of normal intracellular metabolism (e. g., reactive oxygen interme-diates 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 struc-tured DNA, and to coordinate cell-cycle progression with DNA repair. Typically, cell-cycle checkpoint acti-vation slows or arrests cell-cycle progression, thereby al-lowing time for appropriate repair mechanisms to cor-rect 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 in-creases the resistance of immature (CD4,CD8,) T cells to ionizing radiation (IR)-induced apoptosis (Xu and Bal-timore 1996; Hirao et al. 2000). In a broader context, cell-cycle checkpoints can be en-visioned 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 im-portant to recognize that checkpoint surveillance func-tions are not confined solely to the happenings within the nucleus-extranuclear parameters, such as growth factor availability and cell mass accumulation, also gov-ern 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 during cell-cycle progression (Fig. 1). These checkpoints con-tain, as their most proximal signaling elements, sensor proteins that scan chromatin for partially replicated

Cell cycle checkpoint signaling through the ATM and ATR kinases