TSC loss distorts DNA replication programme and sensitises cells to genotoxic stress
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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
Govind M. Pai, email: firstname.lastname@example.org
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
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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