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

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)