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Evaluation of metabolic alterations in human cells from patients with Trichothiodystrophy with deficiency in nucleotide excision repair

Grant number: 22/02400-5
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2022
Effective date (End): September 01, 2024
Field of knowledge:Biological Sciences - Genetics - Mutagenesis
Principal Investigator:Carlos Frederico Martins Menck
Grantee:Vitória Rezende Goll
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:19/19435-3 - The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg), AP.TEM
Associated scholarship(s):22/13690-4 - Organoids and neural progenitor cells development to study XPD-mutated trichothiodystrophy, BE.EP.IC


The DNA molecule is injured by exogenous and endogenous factors, and the Nucleotide Excision Repair (NER) pathway is one of the cells' mechanisms that remove some of those lesions and help to maintain the genome integrity. The TFIIH complex is one of the NER components and is involved in both DNA repair and transcription. Among other proteins, the XPD and XPB helicases are core components of TFIIH. Mutations in the ERCC2/XPD gene that encodes the helicase XPD are related to some genetic syndromes such as xeroderma pigmentosum (XP), Trichothiodystrophy (TTD), and other deleterious syndromes. TTD patients usually present brittle hair, ichthyosis, photosensitivity, neurological abnormalities (such as intellectual disability), neurodegeneration, decreased fertility, short stature, and premature aging. Premature aging is closely related to transcription problems, and reactive oxygen species (ROS) are among the main candidates for causing lesions that cause transcription deficiency. Some oxidative stress injuries can be repaired by NER, and XPD cells have been described as sensitive to oxidative stress induction. Then, the TTD susceptibility to oxidative stress and the evidence that XPD is present in mitochondria support the idea of possible mitochondrial dysfunctions in TTD cells, and these have been described in other premature aging and neurodegenerative diseases. Moreover, considering the role of pyruvate as an antioxidant and its importance in energetic metabolism regulation, we propose to test whether the supplementation with this component may interfere with deleterious phenotypes observed in TTD cells. Based on studies that use sodium pyruvate as a treatment for mitochondrial diseases, we propose to test the hypothesis that ERCC2/XPD-mutated cells from TTD individuals show metabolic alterations due to mitochondrial dysfunctions and that this phenotype can be modified by supplementation of the culture medium with sodium pyruvate.(AU)

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