Tel1/ATM prevents degradation of replication forks that reverse after topoisomerase poisoning |
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| Authors: | Luca Menin Sebastian Ursich Camilla Trovesi Ralph Zellweger Massimo Lopes Maria Pia Longhese Michela Clerici |
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| Affiliation: | 1. Dipartimento di Biotecnologie e Bioscienze, Università di Milano‐Bicocca, Milano, Italy;2. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland |
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| Abstract: | 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 tel1Δ cells without affecting fork reversal in wild‐type cells. Moreover, Mrc1 inactivation prevents fork reversal in wild‐type, tel1Δ, and mre11 nuclease‐deficient cells and relieves the hypersensitivity of tel1Δ 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. |
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| Keywords: | camptothecin fork reversal Mrc1
MRX
Tel1 |
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