MOD_PIKK_1

The PIKKs are a group of ancient eukaryotic protein kinases including ATM, ATR and DNA-PK. These proteins are characterized by their large size (>200 KDa) and by the presence of a highly conserved phosphoinositide 3-kinase-like catalytic domain. They appear to function principally as protein kinases, however (Yang,2004). PIKKs are the principal components of the DNA damage checkpoint pathway and are probably present in all eukaryotes. The common phosphorylation site for PIKKs is a serine or threonine followed by a glutamine residue, a motif commonly dubbed ...[S/T]Q... (Kim,1999). Often substrate regions are characterized by high local density of SQ/TQ motifs that have been termed "SCDs" (SQ/TQ cluster domains). While sharing the same substrate specificity, the PIKK family members are activated by different checkpoint responses. ATM is involved in the checkpoint response to ionizing radiation, DNA double strand breaks and in V(D)J recombination, while ATR seems to play a primary role in checkpoints induced by UV irradiation or DNA replication blocks. DNA-PK, which has essential functions in V(D)J recombination as well as in non-homologous end joining, is also associated with the checkpoint response (Yang,2004). In general it is often found that the same substrate is phosphorylated by both ATM and ATR in a cell cycle and time dependent manner.