Maiello, Daniela (2024) Molecular mechanisms underlying the functional role of the human DKC1 gene in dyskeratosis congenita and cancer diseases. [Tesi di dottorato]

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Abstract

Dyskerin, a highly conserved pseudouridine synthase, plays a pivotal role in diverse cellular functions by catalyzing the conversion of specific uridines to pseudouridines. The intricate associations of dyskerin with proteins like GAR1, NHP2, and NOP10, along with small non-coding RNAs, form functional RNPs, including active telomerase, H/ACA small nucleolar ribonucleoproteins (snoRNPs), and small Cajal body-specific ribonucleoproteins (scaRNPs). Dyskerin's involvement spans critical cellular processes such as telomere integrity, ribosome biogenesis, IRES-dependent translation, DNA damage response, vesicular trafficking, and energy metabolism. The focus of this study lies in the hereditary disorder X-linked dyskeratosis congenita (X-DC), stemming from hypomorphic mutations of the DKC1 gene encoding dyskerin. This research study has revealed a previously unknown interdependence between mTOR signaling and UPR during a pathological process initiated by reduced levels of dyskerin. The findings of this project highlight a unique and significant connection between dyskerin, autophagy, and UPR, which could potentially have far-reaching implications for our understanding of cellular mechanisms. This discovery sheds new light on the complex interplay of the mTOR signaling pathway and UPR, which could be important for developing new therapeutic interventions in the future. The present study endeavors to explore the functions of dyskerin, particularly its interaction with CypA, and the consequent potential opportunities to address the intricacies of dyskeratosis Congenita X-linked and allied cellular processes in various disease contexts.

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