Association between oxidative stress and nucleotide excision DNA repair related syndromes

• Grant number: 11/13872-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: March 01, 2012
• End date: January 31, 2014
• Field of knowledge: Biological Sciences - Genetics
• Principal Investigator: Carlos Frederico Martins Menck
• Grantee: Camila Carriao Machado Garcia
• Host 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 most studied repair pathway as the nucleotide excision repair (NER) that removes a wide variety of lesions that distort the double helix, such as pyrimidine dimers (CPDs and 6-4PPs) generated by UV radiation, which represents 8 % of solar radiation that covers the Earth surface. NER is divided into two subways: global genome repair (GGR) is responsible for removal the lesions present in any area of the genome, and transcription coupled repair (TCR) that removes adducts present in transcriptionally active genes. Many proteins are associated with this route, performing functions from the recognition of the injury, its removal and insertion of a new DNA strand. The XPA protein, for example, is recruited at the removal adducts stage and, therefore, cells deficient in this protein does not exhibit any of two NER subways. While, XPC and CSA proteins are involved in the recognition mechanisms associated with GGR and TCR, respectively. It is known that patients with mutations in some genes that encode NER proteins, such as XPA and XPC develop xeroderma Pigmentosum, a syndrome characterized by high skin cancer incidence. However, patients with mutations in CSA and CSB (Cockayne syndrome) is characterized by neurodegeneration and premature aging, accompanied by the absence of tumors. For this reason, studying the effect of radiation and redox stress-inducing substances in cells and animals NER deficient proteins is an important tool to understand the mechanisms of diseases progression, tumors incidence, neurodegeneration and aging. It is in this context that this project, to investigate the mechanisms of cell death that may be associated with redox imbalance in NER deficient human cells and animals, in order to clarify the importance of oxidative stress and lipid peroxidation in the mechanisms involving disease progression. We also hope to contribute to understanding the possible association of the NER proteins in the repair of DNA adducts caused by redox imbalance and the involvement of CSA and CSB proteins in response to oxidative stress.