title: Cells deficient in base-excision repair reveal cancer hallmarks originating from adjustments to genetic instability.
abstract: Genetic instability, provoked by exogenous mutagens, is well linked to initiation of cancer. However, even in unstressed cells, DNA undergoes a plethora of spontaneous alterations provoked by its inherent chemical instability and the intracellular milieu. Base excision repair (BER) is the major cellular pathway responsible for repair of these lesions, and as deficiency in BER activity results in DNA damage it has been proposed that it may trigger the development of sporadic cancers. Nevertheless, experimental evidence for this model remains inconsistent and elusive. Here, we performed a proteomic analysis of BER deficient human cells using stable isotope labelling with amino acids in cell culture (SILAC), and demonstrate that BER deficiency, which induces genetic instability, results in dramatic changes in gene expression, resembling changes found in many cancers. We observed profound alterations in tissue homeostasis, serine biosynthesis, and one-carbon- and amino acid metabolism, all of which have been identified as cancer cell 'hallmarks'. For the first time, this study describes gene expression changes characteristic for cells deficient in repair of endogenous DNA lesions by BER. These expression changes resemble those observed in cancer cells, suggesting that genetically unstable BER deficient cells may be a source of pre-cancerous cells.
authors: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom.
authors: Enni
authors: E
authors: Markkanen
authors: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom.
authors: Roman
authors: R
authors: Fischer
authors: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Lavrenteva 10, 630090 Novosibirsk, Russia.
authors: Marina
authors: M
authors: Ledentcova
authors: Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, United Kingdom.
authors: Benedikt M
authors: BM
authors: Kessler
authors: Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ, United Kingdom Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Lavrenteva 10, 630090 Novosibirsk, Russia grigory.dianov@oncology.ox.ac.uk.
authors: Grigory L
authors: GL
authors: Dianov
mesh_terms: D000596:Amino Acids / Q000096:biosynthesis / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D020552:Comet Assay; D017931:DNA Primers; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D004734:Energy Metabolism; D042822:Genomic Instability; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D000596:Amino Acids; D017931:DNA Primers; D004268:DNA-Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1