Phosphoregulation of the checkpoint kinase Mec1^ATR

Yeast Mec1, and its mammalian ortholog, Ataxia-Telangiectasia and Rad3-related, are giant protein kinases central to replication stress and double strand DNA break repair. Mec1^ATR, in complex with Ddc2^ATRIP, is a 'sensor' of single stranded DNA, and phosphorylates numerous cell cycle and DNA repair factors to enforce cell cycle arrest and facilitate repair. Over the last several years, new techniques - particularly in structural biology - have provided molecular mechanisms for Mec1^ATR function. It is becoming increasingly clear how post-translational modification of Mec1^ATR and its interaction partners modulates the DNA damage checkpoint. In this review, we summarise the most recent work unravelling Mec1^ATR function in the DNA damage checkpoint and provide a molecular context for its regulation by phosphorylation.