The RecQ DNA helicase Rqh1 promotes Rad3^ATRkinase signaling in the DNA replication checkpoint pathway of fission yeast

Rad3 is the orthologue of ATR and the sensor kinase of the DNA replication checkpoint inSchizosaccharomyces pombe. Under replication stress, it initiates checkpoint signaling at the forks necessary for maintaining genome stability and cell survival. To better understand the checkpoint initiation process, we have carried out a genetic screen in fission yeast by random mutation of the genome looking for mutants with defects in Rad3 kinase signaling. In addition to the previously reportedtel2-C307Ymutant (1), this screen has identified six mutations inrqh1encoding a RecQ DNA helicase. Surprisingly, theserqh1mutations except a start codon mutation are all in the helicase domain, indicating that the helicase activity of Rqh1 plays an important role in the replication checkpoint. In support of this notion, integration of two helicase-inactive mutations or deletion ofrqh1generated a similar Rad3 signaling defect and heterologous expression of human RECQ1, BLM and RECQ4 restored the Rad3 signaling and partially rescued arqh1helicase mutant. Therefore, the replication checkpoint function of Rqh1 is highly conserved and mutations in the helicase domain of these human enzymes may cause the checkpoint defect and contribute to the cancer predisposition syndromes.