A single S phase double-strand break influences replicon dynamics and triggers a Mre11-Tel1/ATM-mediated mechanism controlling terminal fork integrity

摘要

SummaryIn response to replication stress, the Mec1/ATR and SUMO pathways control the stalled and damaged fork stability. We investigated the S phase response at forks encountering a broken template (termed terminal fork). We show that double strand break (DSB) formation can locally trigger dormant origin firing. Irreversible fork resolution at the break does not impede progression of the other fork in the same replicon (termed sister fork). The Mre11-Tel1/ATM response acts at terminal forks preventing accumulation of cruciform DNA intermediates that tether sister chromatids and can undergo nucleolytic processing. We conclude that sister forks can be uncoupled during replication and that, following DSB-induced fork termination, replication is rescued by dormant origin firing or adjacent replicons. We have uncovered a Tel1/ATM and Mre11-dependent response controlling terminal fork integrity. Our findings have implications for those genome instability syndromes that accumulate DNA breaks during S phase and for forks encountering eroding telomeres.