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Responses to genome aldehyde adducts generating agents of cells from Cockayne Syndrome patients

Grant number: 23/00266-2
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): March 01, 2023
Effective date (End): January 31, 2025
Field of knowledge:Biological Sciences - Genetics - Mutagenesis
Acordo de Cooperação: Netherlands Organisation for Scientific Research (NWO)
Principal Investigator:Carlos Frederico Martins Menck
Grantee:Orlando Soares Louzada Neto
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


DNA repair systems act on genome integrity maintenance upon exposure to internal and external mutagenic agents. Deficiencies in these systems may lead to premature aging and neurodegeneration in Cockayne syndrome (CS) patients. CS is a recessive autosomal disease caused by mutations mainly in ERCC6 and ERCC8 genes. Both genes codeproteins enrolled on the first step of transcription-coupled nucleotide excision repair (NER). Thus, CS patients suffer from solar light sensitivity and display several clinical symptoms, which result in developmental problems and premature aging features. Since the neural system is not directly susceptible to damage from ultraviolet radiation, we believe that RNA transcription problems on damaged DNA by intracellular agents may be responsible for these clinical phenotypes, including neurological ones. The idea of this proposal is to evaluate the cellular responses to genome damage caused by formaldehyde (a by-product of cell metabolism). DNA adducts caused by aldehydes and formaldehyde are similar, so the latter can be used to mimic endogenously generated damage. In this project, we intend to evaluate how these types of DNA damage can affect the transcription process and cell cycle progression on fibroblasts, neuron precursor cells (NPC), and induced-pluripotent stem cells(iPSC) from CS patients, comparing these effects with similar DNA repair proficient (WT) cells. Additionally, we intend to knock out ALDH2 and ALDH5 genes (both acting on aldehydes clearance) using CRISPR/Cas9 technology. The responses to formaldehyde treatment and oxidative stress induction (a possible aldehyde-like generator) in the resulting mutant CS cells will also be investigated. The phenotype of these cells can also be evaluated in low-oxygen cultures. We hope that these results support not only a better understanding of CS biology and its phenotypical singularities, but also how transcription works on human cells, including those directly associated with the central nervous system. (AU)

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