The FHA Domain in DNA Repair and Checkpoint Signaling

Since the discovery of the genetic control of cell cyclecheckpoints by Weinert and Hartwell in 1988, intense efforts have focused on the identification of genes involvedin mediating cell cycle arrest or delay in response to DNAdamage or replication block. Most of this pioneeringwork has been carried out initially in the budding yeastSaccharomyces cerevisiae and in the fission yeastSchizosaccharomyces pombe. The identification of protein kinases as integral players in the checkpoint responses (Zhou and Elledge 1993; Allen et al. 1994; Katoand Ogawa 1994; Weinert et al. 1994; Paulovich andHartwell 1995; Sun et al. 1996) led to a paradigm inwhich checkpoint signaling is analogous to other classical signaling pathways (Carr 1997). In this model (Lowndes and Murguia 2000), DNA damage (or structures arising from its repair) is recognized by an elusive sensormachinery. This sensor, which has been associated withthe products of the S. cerevisiae RAD24, RAD17, andRAD9 epistasis groups, somehow activates a checkpointprotein kinase cascade. This is believed to be initiated bythe activation of the PI3-kinase-like protein kinases of theATM/DNA-PKcs family (Mec1p and Tel1p in the budding yeast). These kinases appear to transmit the "damage" signal to the kinases of the Chk1p and Rad53p families, which are next thought to directly phosphorylatekey mitotic components and repair proteins in order totrigger and establish the cell cycle checkpoint and tomodulate DNA repair events...