Mec1 and Tel1: an arresting dance of resection.

D NA double-stranded breaks (DSBs) are a nasty form of damage for a cell, and their repair is important, complex and deeply studied. In the best case, a DSB is repaired using a homologous substrate; less optimally by error-prone direct sealing, then by sealing to another piece of DNA, or not sealed at all. The key is that cells convert a DSB into ssDNA, a substrate repairable by homology, and cells best undergo cell cycle arrest while doing so; ssDNA and time enable faithful repair. Once repair is complete, the cell resumes division. How cells coordinate resection and arrest is the subject of a study by Clerici et al (2013). They examine, as have others, the multiple roles of upstream-acting checkpoint protein kinases Mec1 and Tel1 (the budding yeast orthologs of mammalian ATR and ATM). Models posited partially explain resection and arrest: Tel1 senses damage at DSBs and assists in initial resection (with other nucleases) to generate ssDNA, that then turns over checkpoint control to Mec1 (which is activated by the ssDNA). Activated Mec1 then phosphorylates downstream protein kinases leading to cell cycle arrest and regulation of repair proteins. What’s left to learn? Plenty, when one examines the details closely as Clerici et al do! An earlier study indicated mutually exclusive activities of Mec1 and Tel1 at telomeres (Takata et al, 2004). Clerici et al also find roles for Mec1 and Tel1 at DSBs; they detail how Mec1 can limit resection and, most surprisingly, show that Tel1 acts in arrest both before and now after Mec1 activity. These results add interesting molecular details to our understanding of DSB metabolism, and pose intriguing puzzles. To study the complexity of Mec1 and Tel1 interactions, the authors make use of the somewhat enigmatic phenomenon called ‘adaptation’; cells with a DSB that cannot be repaired first arrest in G2 (for ~8–12 h), yet they then resume cell division with the broken chromosome (Sandell & Zakian, 1993; Toczyski et al, 1997). Clerici et al first identify a Mec1 mutant they call mec1-ad, that ‘fails to adapt’, that is cells experience a prolonged arrest with a broken chromosome. They found, as have others, that this prolonged arrest (failure to adapt) does occur through canonical checkpoint activation (i.e. downstream Rad53 checkpoint kinase is activated), suggesting study of this abnormal prolonged arrest in mec1-ad mutants may reveal aspects of normal signaling.