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The effect of photo-removal of specific lesions induced by ultraviolet light in DNA repair deficient mice

Grant number: 13/13720-1
Support type:Scholarships in Brazil - Master
Effective date (Start): September 01, 2013
Effective date (End): August 31, 2015
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Carlos Frederico Martins Menck
Grantee:Gustavo Satoru Kajitani
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:09/52417-7 - Cell responses to genome damage, AP.TEM

Abstract

The DNA molecule, which contains the genetic information of the living organisms, is frequently damaged, which can elicit effects such as cell death or mutagenesis. One of the main physical factors that can generate lesions in the genetic material is UV irradiation, which generates mainly two types of lesions in the DNA molecule, the ciclobutane pyrimidine dimers (CPDs) and the pyrimidine (6-4) pyrimidone photoproducts (6-4PPs). These UV lesions distort the DNA double-helix structure, and in doing so interfere in essential cellular processes. Among the mechanisms to repair these kind of lesions are the photolyases, enzymes capable of removing these damages through a specific and direct pathway; CPD photolyases and 6-4PP photolyases are responsible for removing only CPDs or 6-4PPs, respectively. These enzymes are absent in placental mammals, in which photolesions are removed by the Nucleotide Excision Repair (NER) pathway. The NER pathway is further divided in two subpathways, the Global Genome Repair (GG-NER), that recognizes lesions all over the genome, and the Transcription Coupled Repair (TC-NER), that recognizes lesion only on transcriptionally active strands. The goal of this work is to study the specific role of each photolesion on the skin of NER knockout (KO) mice. In this work, we shall use XPA KO and CSA KO mice, deficient in NER and TC-NER pathway, respectively. Both lineages are transgenic and expressa gene that codify to one of the photolyases, in order to analyze the effect of each of these lesions after UVB irradiation, in vivo. In this project, the effects of the persistence of each photolesion on mice skin will be analyzed through quantification of cell proliferation, apoptosis, hyperplasia, pigmentation and tumorigenesis after the removal of either CPDs or 6-4PPs.