Sae2 Function at DNA Double-Strand Breaks Is Bypassed by Dampening Tel1 or Rad53 Activity

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Genome instability is one of the most pervasive characteristics of cancer cells and can be due to DNA repair defects and failure to arrest the cell cycle. Among the many types of DNA damage, the DNA double strand break (DSB) is one of the most severe, because it can cause mutations and chromosomal rearrangements. Generation of DSBs triggers a highly conserved mechanism, known as DNA damage checkpoint, which arrests the cell cycle until DSBs are repaired. DSBs can be repaired by homologous recombination, which requires the DSB ends to be nucleolytically processed (resected) to generate single-stranded DNA. In Saccharomyces cerevisiae, DSB resection is initiated by the MRX complex together with Sae2, whereas more extensive resection is catalyzed by both Exo1 and Dna2-Sgs1. The absence of Sae2 not only impairs DSB resection, but also leads to the hyperactivation of the checkpoint proteins Tel1/ATM and Rad53, leading to persistent cell cycle arrest. In this manuscript we show that persistent Tel1 and Rad53 signaling activities in sae2Δ cells cause DNA damage hypersensitivity and defective DSB resection by increasing the amount of Rad9 bound at the DSBs, which in turn inhibits the Sgs1-Dna2 resection machinery. As ATM inhibition has been proposed as a strategy for cancer treatment, the finding that defective Tel1 signaling activity restores DNA damage resistance in sae2Δ cells might have implications in cancer therapies that use ATM inhibitors for synthetic lethal approaches that are devised to kill tumor cells with defective DSB repair.

Vyšlo v časopise: Sae2 Function at DNA Double-Strand Breaks Is Bypassed by Dampening Tel1 or Rad53 Activity. PLoS Genet 11(11): e32767. doi:10.1371/journal.pgen.1005685
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005685

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