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primary topic: Structural and biochemical analysis of the human Rea1-Rsa4 pre-ribosomal complex enables the identification of small molecule inhibitors that impair human cancer cell growth

Structural and biochemical analysis of the human Rea1-Rsa4 pre-ribosomal complex enables the identification of small molecule inhibitors that impair human cancer cell growth
type: Article
abstract: Ribosomes are evolutionary-conserved molecular machines consisting of the large 60S and the small 40S subunits, which follow separate assembly routes but later function together as mature 80S ribosomes during translation. During ribosome biogenesis the pre-60S subunit goes through many maturation steps that require numerous assembly factors. One of them, the AAA+ ATPase Rea1 mediates two crucial remodelling steps in the nucleolus and the nucleoplasm, respectively, by binding via its MIDAS domain to the UBL domains of either Ytm1 (WDR12 in humans) or Rsa4 (NLE1 in humans). These interactions, which are similar to a typical integrin-ligand binding mechanism, are essential for cell growth, and their abolishment confers a lethal phenotype in yeast. Loss-of-function mutations of ribosomal proteins can lead to diseases called Ribosomopathies and growth factors and mitogenic stimuli can alter oncogenic signalling pathways by hyper-activating the tightly regulated ribosome biogenesis process, which, recently, has become a cancer therapy target. Therefore, analyzing the human ribosome assembly pathway might help find small chemical compounds impairing ribosome synthesis at specific maturation stages, which could be exploited for analytical and therapeutic purposes. During my PhD, I could reconstitute the interaction between human homologs of Rea1-MIDAS and Rsa4-UBL domains in vitro and crystallize this heterodimer. Using a dominant-negative rsa4 mutant, mapping the amino acid 85 of the UBL domain, I could impair this interaction, which allowed me to evaluate the effects of the loss of Rea1-MIDAS-Rsa4-UBL binding in vitro and human culture cells. I successfully crystallized the complex, obtaining the atomic model of the MIDAS-UBL interaction, a central finding supporting the search for small chemical compounds impairing the human Rea1-MIDAS-Rsa4-UBL interaction. Eventually, we could find one inhibitor, which I tested in vitro and human cancer cells. In addition, using the dom…
date: 2024
author list: authors
type: EPrint
type: DoctoralThesisEPrint
is part of: repository
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Structural and biochemical analysis of the human Rea1-Rsa4 pre-ribosomal complex enables the identification of small molecule inhibitors that impair human cancer cell growth (PDF)
type: Document
has file: Federica thesis 19-10-2022.pdf
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Federica Fiorentino
type: Person
given name: Federica
family name: Fiorentino

Structural and biochemical analysis of the human Rea1-Rsa4 pre-ribosomal complex enables the identification of small molecule inhibitors that impair human cancer cell growth (Other)
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Structural and biochemical analysis of the human Rea1-Rsa4 pre-ribosomal complex enables the identification of small molecule inhibitors that impair human cancer cell growth (Other)
type: Document
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Structural and biochemical analysis of the human Rea1-Rsa4 pre-ribosomal complex enables the identification of small molecule inhibitors that impair human cancer cell growth (Other)
type: Document
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Structural and biochemical analysis of the human Rea1-Rsa4 pre-ribosomal complex enables the identification of small molecule inhibitors that impair human cancer cell growth (Other)
type: Document
is version of: Structural and biochemical analysis of the human Rea1-Rsa4 pre-ribosomal complex enables the identification of small molecule inhibitors that impair human cancer cell growth (PDF)
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Structural and biochemical analysis of the human Rea1-Rsa4 pre-ribosomal complex enables the identification of small molecule inhibitors that impair human cancer cell growth (Other)
type: Document
is version of: Structural and biochemical analysis of the human Rea1-Rsa4 pre-ribosomal complex enables the identification of small molecule inhibitors that impair human cancer cell growth (PDF)
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primary topic: Structural and biochemical analysis of the human Rea1-Rsa4 pre-ribosomal complex enables the identification of small molecule inhibitors that impair human cancer cell growth