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P53-hHR23B-XPC axis in DNA repair modulation in melanomas: evidences to carcinogenic, progression and chemoresistnce process

Grant number: 10/16901-9
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): January 01, 2011
Effective date (End): December 31, 2013
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Roger Chammas
Grantee:Guilherme Francisco
Home Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Malignant melanoma is a cancer that affects the existing melanocytes in the skin, and is characterized by high rate of mortality and low response to chemotherapy treatments. Among the factors related to the development of melanoma are the damage caused by exposure to ultraviolet radiation present in sunlight, which cause DNA damage that can lead to fixation of mutations. This damage is usually repaired by the Nucleotide excision repair pathway (NER), the genes involved are related to the Xeroderma pigmentosum syndrome, where individuals with mutated genes are susceptible to skin tumors in young ages. Not only referring to the carcinogenesis process, repair genes via NER can also be related to chemoresistance presented by melanomas. Towards NER, two genes has great importance in recognizing the lesions caused by UV: XPC and hHR23B. While XPC is described as the protein that recognizes the damage and start the repair process, hHR23B acts in the stabilization of XPC, protecting it from proteasome degradation and is also described by acting in the delivery of ubiquitinated proteins for degradation through proteasome. In addition to the direct relationship between XPC and hHR23B, p53 also plays a critical role in modulation to interact and modulate the activity of the initial steps of NER. Previous studies in our group have indicated that XPC polymorphisms can be related to increased susceptibility to melanoma. Given these results, this project intends to extend the analysis of the importance of the first steps of the NER pathway in the development of melanoma and also in disease progression. To do this we will study the functional polymorphisms of XPC, checking for the presence of these genetic variations alter mRNA stability. In addition, as the hHR23B, intends to verify the role of protein in carcinogenesis process, progression and chemoresistance. In this context, the role of the modular largest NER activity, p53 also be exploited. Thus, this project aims to increase knowledge on the role of DNA repair system in melanoma biology.