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Tel1/ ATM prevents degradation of replication forks that reverse after topoisomerase poisoning
Author(s) -
Menin Luca,
Ursich Sebastian,
Trovesi Camilla,
Zellweger Ralph,
Lopes Massimo,
Longhese Maria Pia,
Clerici Michela
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201745535
Subject(s) - humanities , library science , art , computer science
In both yeast and mammals, the topoisomerase poison camptothecin ( CPT ) induces fork reversal, which has been proposed to stabilize replication forks, thus providing time for the repair of CPT ‐induced lesions and supporting replication restart. We show that Tel1, the Saccharomyces cerevisiae orthologue of human ATM kinase, stabilizes CPT ‐induced reversed forks by counteracting their nucleolytic degradation by the MRX complex. Tel1‐lacking cells are hypersensitive to CPT specifically and show less reversed forks in the presence of CPT . The lack of Mre11 nuclease activity restores wild‐type levels of reversed forks in CPT ‐treated tel1 Δ cells without affecting fork reversal in wild‐type cells. Moreover, Mrc1 inactivation prevents fork reversal in wild‐type, tel1 Δ , and mre11 nuclease‐deficient cells and relieves the hypersensitivity of tel1 Δ cells to CPT . Altogether, our data indicate that Tel1 counteracts Mre11 nucleolytic activity at replication forks that undergo Mrc1‐mediated reversal in the presence of CPT .