Abstract
Human cells are continuously threatened by endogenous and exogenous assaults on DNA. Following various DNA damages, PI3-kinase related protein kinases (PIKKs), including ATM, ATR and DNA-PKcs, take key roles in the DNA damage response (DDR). DNA double strand break (DSB) is a deleterious damage for cell survival and genome integrity, and major pathways for its repair are non-homologous end-joining (NHEJ) and homologous recombination (HR). ATM is critical for checkpoint signaling and DSB repair, especially HR, and DNA-PKcs is an essential component of NHEJ. ATR is activated by RPA-coated single-stranded DNA (ssDNA) that appears at a stalled replication fork (replication stress), and phosphorylates downstream factors in the S-phase checkpoint. However, recent studies have revealed that these PIKK family kinases function in conjunction with each other in DDR. For example, in response to DSB induced by ionizing radiation (IR), ATR is activated by ssDNA resulting from DNA end resection in ATM-dependent manner. We have shown that DNA-PKcs is phosphorylated by ATM and ATR in response to exposure to IR and ultraviolet light (UV), respectively. In addition, contrary to the rapid activation of the ATR pathway, delayed activation of ATM and DNA-PKcs kinases after UV-induced replication stress was found, suggesting that DNA double strand end (one-ended DSB) produced by replication fork collapse triggered their kinase activity. With a focus on our recent works, roles of PIKKs and their substrates in DSB response will be discussed.
