Oncotarget

Research Papers:

TSC loss distorts DNA replication programme and sensitises cells to genotoxic stress

Govind M. Pai _, Alexandra Zielinski, Dennis Koalick, Kristin Ludwig, Zhao-Qi Wang, Kerstin Borgmann, Helmut Pospiech and Ignacio Rubio

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Oncotarget. 2016; 7:85365-85380. https://doi.org/10.18632/oncotarget.13378

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Abstract

Govind M. Pai1, Alexandra Zielinski2, Dennis Koalick3, Kristin Ludwig1, Zhao-Qi Wang3, Kerstin Borgmann2, Helmut Pospiech3,4, Ignacio Rubio1

1Institute of Molecular Cell Biology, Center for Molecular Biomedicine, University Hospital, 07745 Jena, Germany

2Laboratory of Radiobiology & Experimental Radiooncology, Department of Radiotherapy and Radiooncology, Center of Oncology, University Medical Center Hamburg-Eppendorf, Germany, 20246 Hamburg, Germany

3Leibniz Institute on Aging - Fritz Lipmann Institute, 07745 Jena, Germany

4Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014 Oulu, Finland

Correspondence to:

Govind M. Pai, email: m.govind.pai@gmail.com

Ignacio Rubio, email: Ignacio.Rubio@med.uni-jena.de

Keywords: tuberous sclerosis, mTORC1, replication stress, genotoxic stress, adaptive responses

Received: March 04, 2016     Accepted: October 26, 2016     Published: November 16, 2016

ABSTRACT

Tuberous Sclerosis (TSC) is characterized by exorbitant mTORC1 signalling and manifests as non-malignant, apoptosis-prone neoplasia. Previous reports have shown that TSC-/- cells are highly susceptible to mild, innocuous doses of genotoxic stress, which drive TSC-/- cells into apoptotic death. It has been argued that this hypersensitivity to stress derives from a metabolic/energetic shortfall in TSC-/- cells, but how metabolic dysregulation affects the DNA damage response and cell cycle alterations in TSC-/- cells exposed to genotoxic stress is not understood. We report here the occurrence of futile checkpoint responses and an unusual type of replicative stress (RS) in TSC1-/- fibroblasts exposed to low-dose genotoxins. This RS is characterized by elevated nucleotide incorporation rates despite only modest origin over-firing. Strikingly, an increased propensity for asymmetric fork progression and profuse chromosomal aberrations upon mild DNA damage confirmed that TSC loss indeed proved detrimental to stress adaptation. We conclude that low stress tolerance of TSC-/- cells manifests at the level of DNA replication control, imposing strong negative selection on genomic instability that could in turn detain TSC-mutant tumours benign.


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