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Transcription stress and metabolic redesign in rare DNA Repair disorders - Mastroberardino

Transcription stress and metabolic redesign in rare DNA Repair disorders


Our genetic code is constantly threatened by exogenous and endogenous factors that can cause detrimental chemical modifications, i.e. DNA damage, compromising its fidelity. Unrepaired DNA damage has always very serious health consequences that can culminate in cancer and/or accelerated aging. Organisms developed an intricate network of repair mechanisms responsible for amending harmful DNA damage. Genetic defects compromising one of such mechanisms, the nucleotide excision repair pathway (NER), cause severe diseases such as Cockayne syndrome (CS) and xeroderma pigmentosum (XP). These diseases also affect the brain amd cause neurological symptoms that have profound impact on both patients’ and families’ well-being. The exact reasons causing these symptoms, however, are unknown and cannot be explained solely on the basis of defective NER.
In our previous work, we discovered that NER genetic defects cause alterations in the way cells use glucose and, in particular, inhibit a specific series of processes called glycolysis that can very quickly transform glucose in smaller molecules necessary for cell function. Glycolysis is very important for brain function and we hypothesize that its inhibition greatly contributes to neurological dysfunction in CS and XP.
In this project, we will study in greater detail how glucose is used in brains of XP and CS laboratory models, and test the hypothesis that more severe neurological defects are associated with more pronounced inhibition of glycolysis and vice versa. We will also attest the efficacy of pharmacological interventions to restore glucose flux through glycolysis in improving neurological signs.