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Home » Proyectos de investigación » Análisis de la función y de la regulación de la exonucleasa TREX2. Papel en la respuesta al daño en el DNA
Título: Análisis de la función y de la regulación de la exonucleasa TREX2. Papel en la respuesta al daño en el DNA
IP: Dra. Concepció Soler Prat
Resumen del proyecto: Proteins that contain 3’-5’ exonuclease activities are involved directly in maintaining genome stability. They do this by removing mismatched, modified, fragmented and normal base-paired nucleotides. The action of one or more exonucleases is requiered for DNA synthesis, recombination and repair, telomere maintenance, V(D)J recombination, class-switch and somatic hypermutation. Deficiencies or mutations of some exonucleases lead to an increased cancer susceptibility, genomic instability, immune alteration or lethality. The expression of some exonucleases can be critical either for cancer development or for the efficiency of antitumoral therapies based on nucleoside analogues. Despite the numerous 3’-5’ exonucleases present in the cell with putative overlapping activities, in vivo functional studies had revealed non-redundant biological roles for many of these proteins in multiple cellular processes. Among the 3’-5’ exonucleases, biological function of TREX2 is still largely unknown. So far, genotype analyses of TREX2 gene in both prostate cancer and control samples have identified some SNPs (single nucleotide polymorphisms). However, these SNPs occurred at very low frequency and none give rise to TREX2 function alteration. To assess the function of TREX2 in vivo and consequences of its deficiency, we have generated and are characterizing the TREX2 knockout mice. Interestingly, TREX2 knockout mouse is viable and do not show a relevant increase in spontaneous tumour incidence, but rather show an increased susceptibility to induced skin tumorigenesis (Parra et al. Cancer Res 69, 6676-84, 2009). Our results indicate that TREX2 can play a relevant role in the DNA damage response, suggesting a suppressor role in tissues with squamous epithelia, such as skin, tongue, esophagous and cervix. In fact, this tissue’s epithelium is the main target of environmental DNA-damaging agents, from ultraviolet radiation, to pollutants from tobacco smoke, vehicle emissions and industry. Tumors that occur in these tissues are mainly squamous cell carcinomas. The main goal of present project is to analyze whether squamous carcinomas and/or persons with susceptibility to these tumours have mutations in the TREX2 gene. Our studies should determine whether TREX2 might be related with the complex mechanisms of carcinogenesis and could be a new potential target of therapeutic interest.
Entidad financiadora: Ministerio Educación y Ciencia
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