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  • Db model cells showed various aberrant


    Db model cells showed various aberrant phenotypes that seemed to reflect the pathological abnormalities found under diabetic conditions. First, in Db model cells after insulin stimulation, we found the inhibition of the transcriptional repression of the gluconeogenic genes, PCK1 and G6PC, and aberrant glucose production that may constitute a state of “insulin resistance” at the cellular level. Another specific phenotype of Db model cells was a decrease in the phosphorylation level of Akt, a key kinase in the insulin signaling pathway. Collectively, in Db model cells, we found a variety of perturbations related to the pathogenic phenotype of diabetic hepatic cells including typical insulin-resistance and other cell biological and biochemical differences. However, we have not yet elucidated the mutual relationship between these. For example, the effects of a decrease in the PI3P level in Db model cells on specific phenotypes such as a disturbed insulin response and decrease in Akt phosphorylation remain unclear.
    Materials and methods
    Transparency document
    Introduction Genome stability is fundamental for life, and evolution has equipped the cells with many different ways to cope with DNA damage, which occur either spontaneously, due to the intrinsic chemical properties of DNA, endogenously by metabolite reactive products, or after exposure to physical or chemical agents from the environment. Thus, different excision repair pathways can remove structural IL-4, murine recombinant alterations from the DNA molecule, directing the recovery of the original double helix structure. However, these mechanisms are not always completely effective, or simply may not occur before basic DNA processes such as replication or transcription face the damaged templates. In fact, DNA synthesis may be blocked by unrepaired DNA lesions, which can lead to cell death [1,2]. A clever way to avoid such problems is simply sense DNA damage and signal for the cells to stop cell cycle before DNA synthesis or mitosis starts, processes known as cell cycle checkpoints [3]. Still, when DNA damage are not removed and DNA synthesis confronts such obstacles, the cells have mechanisms to signal for repair or allow the DNA to proceed despite of the lesion, helping the cells to tolerate the damage. The relevance of these processes to the protection of organisms is dramatically evidenced by patients with human disorders, who carry mutations that affect directly the mechanisms involved in dealing with damaged DNA. Several clinical phenotypes are often associated with these disorders, but the most commonly observed are increased carcinogenesis and symptoms normally associated with premature aging, including neurological problems and neurodegeneration. Examples of such diseases are the syndromes xeroderma pigmentosum (XP), ataxia telangiectasia (AT) and Fanconi anemia (FA). The three are involved in different processes of DNA damage and present high frequency of cancer, but may also present neurodegeneration phenotypes [[4], [5], [6], [7]] As the focus of this review is DNA synthesis of damaged templates, the example of XP will be detailed. The most prominent symptoms of XP patients affect the skin, where many lesions, including tumors, are frequently observed, but only in regions exposed to the sunlight. Unfortunately, the face is often one of these regions, with severe complications to these patients. XP skin become dry and highly pigmented, and also may develop precancerous lesions, such as actinic keratosis, and tumors (non melanoma and melanoma). Most of the XP patients are defective in the removal of DNA damage, including lesions induced by UV, a process known as Nucleotide Excision Repair (NER). However, some XP patients, who in general have a milder clinical phenotype, were discovered to have normal capacity to remove UV-induced DNA lesions, but their cells failed to replicate efficiently the unrepaired damage [8]. These patients were named XP variants (XP-V). Almost twenty-five years later, the inability of XP-V cells to replicate damaged DNA was demonstrated to be due to a defect on a DNA polymerase responsible for lesions bypass, DNA polymerase eta (Pol eta or Pol η), now known as a translesion synthesis (TLS) DNA polymerase [[9], [10], [11]]. Since this breakthrough, several progresses were made in the understanding of how cells manage to replicate DNA lesions. The need of such mechanisms for cells to cope with DNA damage was revealed by the identification of many other TLS polymerases in human cells. However, their functions are not fully understood yet, leading to many gaps in our knowledge. These gaps are slowly being filled with the discovery of the molecular mechanisms involved in the replication of damaged DNA templates. This review will give an overview of what is known about these TLS polymerases and the strategies known of how they help cells to survive insults, although, in general, at the expense of generating mutations. As the initial experiments were performed with UV-irradiation, most of what is known about these TLS polymerases is related to UV-induced lesions, as detailed below. However, one must bear in mind that other types of DNA damage are also subject to these tolerance mechanisms, and thus the reach of such knowledge may have important impact on cells ability to survive genotoxic agents, including tumor cells resistance to chemotherapeutic agents.