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Tel1/ATM prevents degradation of replication forks that reverse after topoisomerase poisoning


Menin, Luca; Ursich, Sebastian; Trovesi, Camilla; Zellweger, Ralph; Lopes, Massimo; Longhese, Maria Pia; Clerici, Michela (2018). Tel1/ATM prevents degradation of replication forks that reverse after topoisomerase poisoning. EMBO Reports:e45535.

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 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 Δ cells without affecting fork reversal in wild-type cells. Moreover, Mrc1 inactivation prevents fork reversal in wild-type, Δ and nuclease-deficient cells and relieves the hypersensitivity of 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.

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 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 Δ cells without affecting fork reversal in wild-type cells. Moreover, Mrc1 inactivation prevents fork reversal in wild-type, Δ and nuclease-deficient cells and relieves the hypersensitivity of 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Genetics, Biochemistry, Molecular Biology
Language:English
Date:8 May 2018
Deposited On:24 May 2018 09:26
Last Modified:19 Aug 2018 15:46
Publisher:Nature Publishing Group
ISSN:1469-221X
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.15252/embr.201745535
PubMed ID:29739811
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_169959
  • : Project TitleReplication fork remodelling upon cancer-relevant genotoxic stress

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