Two-armed control of ATR, a master regulator of the DNA damage checkpoint
Our genomes encounter DNA damaging events continuously. As damage accumulates, our cells react and stop the cell division process, giving repair mechanisms time to act. To achieve this, two master protein kinases called ATR and ATM, encoded by well-known tumor suppressor genes, activate a cascade of phosphorylation events. The downstream readout of these checkpoint cascades is well characterized, yet the regulation of the master kinase itself has remained enigmatic. Nicole Hustedt, a student in the laboratory of Susan Gasser, examined this question with a combination of sophisticated yeast genetics and phosphoproteomics. She found that the key regulator of the yeast Mec1 kinase, the yeast ATR homologue, is a phosphatase that directly reverses the modification of many damage-induced Mec1 kinase targets. The identified phosphatase, called PP4, not only dephosphorylates Mec1 targets, but directly interacts with the kinase, fine-tuning its activity during the cell cycle.