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.
Highlights
The molecular origin of all cancers lies in mutations in a cell’s DNA sequence [1]
The DNA damage response, which is clearly detected to be activated by XRCC1 knocking down (KD), activates many proteins including transcription factors such as p53, E2F1 and Sp1 as well as a subset of protein kinases, including ATM and AKT (reviewed in e.g. [4,31])
All these proteins induce a cascade of changes that in turn will affect gene expression spectrum bringing cellular metabolism in terms with a new intracellular landscape caused by genetic instability
Summary
The molecular origin of all cancers lies in mutations in a cell’s DNA sequence [1]. genomic instability and mutation is recognised as one of the very few enabling characteristics that clearly drive tumorigenesis by facilitating the acquisition of all other core hallmarks of cancer [2]. The major cellular pathway to safeguard the genome against these frequent and constantly arising DNA lesions is base excision repair (BER), which is responsible for repairing a multitude of different base alterations and DNA single strand breaks (SSBs) [8]. The arising abasic site (AP-site) is further processed by AP-endonuclease 1 (APE1), which cleaves the phosphodiester bond 5 to the AP-site, generating a SSB with a 5 -sugar phosphate. Further processing of this intermediate is carried out by a DNA repair complex that includes DNA polymerase  (Pol ), XRCC1 and DNA ligase IIIa (Lig III). Pol  possesses a dRP- lyase activity that removes the 5 -sugar phosphate and functioning as a DNA polymerase, adds one nucleotide to the 3 -end of the aris-
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