Slx4 and Rtt107 control checkpoint signalling and DNA resection at double-strand breaks

Abstract

The DNA damage checkpoint pathway is acti-vated in response to DNA lesions and replication stress to preserve genome integrity. However, hyper-activation of this surveillance system is detrimental to the cell, because it might prevent cell cycle re-start after repair, which may also lead to senescence. Here we show that the scaffold proteins Slx4 and Rtt107 limit checkpoint signalling at a persistent double-strand DNA break (DSB) and at uncapped telomeres. We found that Slx4 is recruited within a few kilobases of an irreparable DSB, through the interaction with Rtt107 and the multi-BRCT domain scaffold Dpb11. In the absence of Slx4 or Rtt107, Rad9 binding near the irreparable DSB is increased, leading to robust checkpoint signalling and slower nucleolytic degra-dation of the 5 ′ strand. Importantly, in slx4 sae2 double mutant cells these phenotypes are exacer-bated, causing a severe Rad9-dependent defect in DSB repair. Our study sheds new light on the molec-ular mechanism that coordinates the processing and repair of DSBs with DNA damage checkpoint sig-nalling, preserving genome integrity