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Investigating the role of the TG mutation in XPC gene on expression of the transcriptional co-activator PGC-1a

Grant number: 16/15407-7
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): May 01, 2017
Effective date (End): December 31, 2018
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal Investigator:Nadja Cristhina de Souza Pinto
Grantee:Mateus Prates Mori
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Xeroderma pigmentosum (XP) is an inherited autosomal recessive syndrome with a 1,000 fold elevated skin cancer rate in areas exposed to UV light. XP is caused by mutations in one of seven genes (XPA-XPG) of nucleotide excision repair (NER) pathway or in one translesion DNA polymerase (POLH). The XPC protein is a lesion recognition factor in NER, but it has also been shown to interact and stimulate DNA gycosylases OGG1, TDG and SMUG1, to act as transcriptional co-activator and on energy metabolism adaptation. Using XP-C cells we have recently demonstrated that these cells show increased mitochondrial H2O2 production with an adaptive shift between respiratory complexes I and II, leading to increased sensibility towards mitochondrial stress. A surprising finding was a very significant decrease in expression of the transcriptional coactivator PGC-1a (PPARGC1A), which has a major role in controlling mitochondrial biogenesis. In four different XP-C cell lines tested, reduction of PPARGC1A expression was detected in three, all of them carrying the c.1643_1644delTG mutation (”TG) in XPC. In an XP-C cell line carrying a different mutation, we did not observed a reduction of PPARGC1A expression, regardless of nearly absent XPC protein levels, in agreement with results showing that siRNA-mediated XPC knockdown did not alter PPARGC1A expression. Results from other genetic diseases suggest that some mutations can generate new non-coding RNA, with a gain-of-function new molecular phenotype. In this context we propose to investigate: i) the correlation between the ”TG mutation and PPARGC1A expression, expanding the investigation towards other mutations in XPC; ii) the possible epigenetic regulation of this repression; iii) the functional consequences resulting from this possible association between ”TG mutation and the repression of PPARGC1A expression. (AU)

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Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MORI, MATEUS PRATES; DE SOUZA-PINTO, NADJA CRISTHINA. PPRC1, but not PGC-1 alpha, levels directly correlate with expression of mitochondrial proteins in human dermal fibroblasts. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, . (16/15407-7, 17/04372-0, 10/51906-1)
MORI, MATEUS PRATES; DE SOUZA-PINTO, NADJA CRISTHINA. Role of mitochondrial dysfunction in the pathophysiology of DNA repair disorders. Cell Biology International, v. 42, n. 6, SI, p. 643-650, . (17/04372-0, 16/15407-7)
FREIRE, T. S.; MORI, M. P.; MIRANDA, J. N. F. A.; MUTA, L. Y. M.; MACHADO, F. T.; MORENO, N. C.; SOUZA-PINTO, N. C.. Increased H2O2 levels and p53 stabilization lead to mitochondrial dysfunction in XPC-deficient cells. Carcinogenesis, v. 42, n. 11, p. 1380-1389, . (17/04372-0, 18/04471-1, 10/51906-1, 18/26555-2, 19/00480-9, 16/15407-7)
MORI, MATEUS PRATES; DE SOUZA-PINTO, NADJA CRISTHINA. PPRC1, but not PGC-1 alpha, levels directly correlate with expression of mitochondrial proteins in human dermal fibroblasts. GENETICS AND MOLECULAR BIOLOGY, v. 43, p. 10-pg., . (16/15407-7, 10/51906-1, 17/04372-0)
MATEUS PRATES MORI; NADJA CRISTHINA DE SOUZA-PINTO. PPRC1, but not PGC-1α, levels directly correlate with expression of mitochondrial proteins in human dermal fibroblasts. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, . (17/04372-0, 16/15407-7, 10/51906-1)
MORI, MATEUS PRATES; DE SOUZA-PINTO, NADJA CRISTHINA. Role of mitochondrial dysfunction in the pathophysiology of DNA repair disorders. Cell Biology International, v. 42, n. 6, p. 8-pg., . (16/15407-7, 17/04372-0)

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