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Identifier

000428236

Title

The role of DNA damage in mammalian metabolic regulation

Alternative Title

Ο ρόλος της γενωμικής αστάθειας στη ρύθμιση του μεταβολισμού

Author

Ιωαννίδου, Άννα Γ

Thesis advisor

Γαρίνης, Γιώργος

Reviewer

Τσατσάνης, Χρήστος
Παπαματθαιάκης, Ιωσήφ
Δελιδάκης, Χρήστος
Τζαμαρίας, Δημήτρης
Καρδάσης, Δημήτρης
Σπηλιανάκης, Χαράλαμπος
Χαλεπάκης, Γιώργος

Abstract

DNA damage and Immune response are intimately linked with metabolism and the manifestation of age-related pathologies but the underlying mechanisms remain obscure. Using the Cre/LoxP system, we generated a mouse model carrying a defect in ERCC1, the obligatory partner of the structure-specific ERCC1-XPF endonuclease complex, in circulating macrophages. The Er1F/- mice develop normally, but progressively manifest metabolic alterations, including glycogen accumulation and increased tolerance to glucose. We found that accumulation of DNA damage in Er1_F/- macrophages triggers various cytoplasmic stress responses and enhances the biogenesis and secretion of extracellular vesicles (EVs). These EVs are efficiently delivered to the recipient cells where they transfer their cargo, leading to glucose transporter upregulation and increased glucose uptake. In turn, high glucose activates pro-inflammatory signaling, in a rapamycin-sensitive manner, establishing a link between the DNA damage response (DDR), metabolic reprogramming and chronic, systemic inflammation in NER progeroid syndromes

Language

English

Subject

DNA repair

Exosomes

Extracellular vesicles

Glucose

Inflammation

Macrophages

Metabolism

Nucleotide excision repair

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