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RNA modifications and post-transcriptional control in cancer and stem cells

Beneventi, Giulia LU (2021) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Splicing and translation are two of the key steps of post-transcriptional regulation of gene expression. Their tight regulation is essential for development, whereas their deregulation is involved in cancer pathogenesis. Nevertheless, many of the molecular mechanisms controlling these processes are still unknown. Hence, the main aim of this thesis is to elucidate novel regulatory mechanisms that affect splicing and translation in stem and cancer cells.
An emerging layer of regulation is represented by RNA modifications, evolutionarily conserved hallmarks of coding and non-coding RNA. Indeed, small nuclear RNA (snRNA) and ribosomal RNA (rRNA), the RNA components of the spliceosome and ribosome, are decorated with pseudouridines (Ψ) and... (More)
Splicing and translation are two of the key steps of post-transcriptional regulation of gene expression. Their tight regulation is essential for development, whereas their deregulation is involved in cancer pathogenesis. Nevertheless, many of the molecular mechanisms controlling these processes are still unknown. Hence, the main aim of this thesis is to elucidate novel regulatory mechanisms that affect splicing and translation in stem and cancer cells.
An emerging layer of regulation is represented by RNA modifications, evolutionarily conserved hallmarks of coding and non-coding RNA. Indeed, small nuclear RNA (snRNA) and ribosomal RNA (rRNA), the RNA components of the spliceosome and ribosome, are decorated with pseudouridines (Ψ) and 2’-O-methyl groups (2’OMe) within key functional regions. These modifications are introduced by RNA-dependent small ribonucleoproteins (snoRNPs), guided by snoRNAs and scaRNAs. In Paper I I identified the role of the SCARNA15-guided U2 snRNA-Ψ in driving alternative splicing events affecting the pivotal tumor suppressor p53 and redox homeostasis in cancer cells. In Paper II I unraveled the importance of the rRNA pseudouridylation machinery for the homeostasis of the hematopoietic system and the reconstitution capacity of HSCs in vivo. In Paper III I discovered a developmentally regulated 28S rRNA-2’OMe guided by SNORD123. The loss of this modification affected hESCs differentiation and caused translation defects perturbing the resistance to A-site specific antibiotics in fibroblasts. In Paper IV I highlighted a novel interplay between splicing and translation. Here, I uncovered a translationally regulated splicing factor, SF3A3, upon oncogenic stress which affects splicing of genes contributing to mitochondrial homeostasis and metabolism and that influences tumorigenesis of MYC-driven breast cancer.
In sum, this doctoral thesis explores novel post-transcriptional regulatory mechanisms, especially involving RNA modification modulation and dysregulation, with the aim to broaden the knowledge on stem and cancer cells functioning and to contribute to the discovery of future clinical implications. (Less)
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author
supervisor
opponent
  • Assistant Professor Roignant, Jean-Yves, Center of Integrative Genomics, Lausanne University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
RNA modifications, Pseudouridine, 2’-O-methylation, Splicing, Translation, non-coding RNAs, Cancer, Stem cells, Differentiation, Stress response
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2021:131
pages
82 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/63465952109?pwd=V1QwTGNySElIbVRGSXZhZG4rampsdz09
defense date
2021-12-08 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-138-3
language
English
LU publication?
yes
id
78cf37fa-1af6-4c08-92da-c1f86f373756
date added to LUP
2021-10-22 16:53:46
date last changed
2021-11-17 09:13:58
@phdthesis{78cf37fa-1af6-4c08-92da-c1f86f373756,
  abstract     = {{Splicing and translation are two of the key steps of post-transcriptional regulation of gene expression. Their tight regulation is essential for development, whereas their deregulation is involved in cancer pathogenesis. Nevertheless, many of the molecular mechanisms controlling these processes are still unknown. Hence, the main aim of this thesis is to elucidate novel regulatory mechanisms that affect splicing and translation in stem and cancer cells.<br/>An emerging layer of regulation is represented by RNA modifications, evolutionarily conserved hallmarks of coding and non-coding RNA. Indeed, small nuclear RNA (snRNA) and ribosomal RNA (rRNA), the RNA components of the spliceosome and ribosome, are decorated with pseudouridines (Ψ) and 2’-O-methyl groups (2’OMe) within key functional regions. These modifications are introduced by RNA-dependent small ribonucleoproteins (snoRNPs), guided by snoRNAs and scaRNAs. In Paper I I identified the role of the SCARNA15-guided U2 snRNA-Ψ in driving alternative splicing events affecting the pivotal tumor suppressor p53 and redox homeostasis in cancer cells. In Paper II I unraveled the importance of the rRNA pseudouridylation machinery for the homeostasis of the hematopoietic system and the reconstitution capacity of HSCs in vivo. In Paper III I discovered a developmentally regulated 28S rRNA-2’OMe guided by SNORD123. The loss of this modification affected hESCs differentiation and caused translation defects perturbing the resistance to A-site specific antibiotics in fibroblasts. In Paper IV I highlighted a novel interplay between splicing and translation. Here, I uncovered a translationally regulated splicing factor, SF3A3, upon oncogenic stress which affects splicing of genes contributing to mitochondrial homeostasis and metabolism and that influences tumorigenesis of MYC-driven breast cancer.<br/>In sum, this doctoral thesis explores novel post-transcriptional regulatory mechanisms, especially involving RNA modification modulation and dysregulation, with the aim to broaden the knowledge on stem and cancer cells functioning and to contribute to the discovery of future clinical implications.}},
  author       = {{Beneventi, Giulia}},
  isbn         = {{978-91-8021-138-3}},
  issn         = {{1652-8220}},
  keywords     = {{RNA modifications; Pseudouridine; 2’-O-methylation; Splicing; Translation; non-coding RNAs; Cancer; Stem cells; Differentiation; Stress response}},
  language     = {{eng}},
  number       = {{2021:131}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{RNA modifications and post-transcriptional control in cancer and stem cells}},
  url          = {{https://lup.lub.lu.se/search/files/109600476/Giulia_Beneventi_Thesis_WEBB.pdf}},
  year         = {{2021}},
}