TopBP1 Play A Key Role In Cell Signaling With DNA Damage

ObjectiveIn response to DNA damage or replication stalling, cells activate genome surveillance pathways that cooperate to preserve genomic integrity. One such pathway is the ATR signaling cascade. In this pathway, ATR phosphorylates and activates a number of downstream targets that coordinate cell cycle progression with DNA repair. One such target is Chk1, a kinase that amplifies the ATR signaling and directs it to the desired cell cycle and DNA repair effectors. Chk1 is phosphorylated by ATR on ser-ines 317 and 345 in a DNA damage dependent manner. These phosphoryl-ations are critical for Chk1 activation, but may also play other roles such as promoting Chk1 dissociation form chromatin or restraining Chk1 export from cell nuclei. Once activated, Chk1 induces degradation of Cdc25A, followed by inhibition of cyclin dependent kinases (CDKs) and cell cycle delay. Such a rapid and reversible cell cycle arrest is believed to be essential to provide time for efficient DNA repair. Besides having an important role in the cellular response to exogenous DNA damage, the ATR—Chk1—Cdc25A—Cdk pathway has a well—established role in the unperturbed cell cycle as well. Thus, disruption of either ATR or Chkl genes is embryonically lethal in mice. On the cellular level, siRNA— or drug—mediated inhibition of Chk1 activity also leads to unscheduled DNA replication resulting in massive DNA damage and phosphorylation of ATR targets. Thus, the ATR—Chk1 pathway appears essential to monitor the fidelity of the replication process.