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Decoding the RNA regulome governing cellular stress responses and cell fate transitions

Madej, Magdalena LU (2025) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
RNA modifying enzymes play a pivotal role in reshaping gene expression programs in response to diverse intracellular and extracellular cues, thereby maintaining cellular homeostasis. When dysregulated, these enzymes are increasingly implicated in the onset and progression of various diseases. While traditionally recognised for their catalytic functions, mounting evidence suggests that many RNA modifying enzymes exhibit additional non-catalytic “moonlighting” activities. However, the full extent of their multifunctionality remains poorly understood.
In the first study, I defined a previously unrecognized role for pseudouridine synthase 10 (PUS10) in regulating the innate immune response. Using in vitro and in vivo model systems, I... (More)
RNA modifying enzymes play a pivotal role in reshaping gene expression programs in response to diverse intracellular and extracellular cues, thereby maintaining cellular homeostasis. When dysregulated, these enzymes are increasingly implicated in the onset and progression of various diseases. While traditionally recognised for their catalytic functions, mounting evidence suggests that many RNA modifying enzymes exhibit additional non-catalytic “moonlighting” activities. However, the full extent of their multifunctionality remains poorly understood.
In the first study, I defined a previously unrecognized role for pseudouridine synthase 10 (PUS10) in regulating the innate immune response. Using in vitro and in vivo model systems, I demonstrated that PUS10 deficiency leads to upregulation of interferon-stimulated genes (ISGs). Mechanistically, PUS10 utilizes a specific subset of tRNA-derived small RNAs (tdRs) to regulate translation and suppress the expression of endogenous retroelements. PUS10 loss triggers activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, likely via RNA-DNA hybrids accumulation. Furthermore, I uncovered a transcriptional signature associated with PUS10 that correlates with autoimmune disease. Together, these findings identify PUS10 as a novel regulator of viral mimicry and immune balance.
Based on prior evidence, I discovered that PUS10 depletion affects DNA damage response (DDR) signalling pathways, sensitizes cells to DNA damage-induced cell death and disrupts cell cycle progression. PUS10 appears to influence DNA repair pathway choice by suppressing error-prone non-homologous end joining (NHEJ) and favouring high-fidelity homologous recombination (HR). Beyond genome maintenance, PUS10 modulates cell fate transitions by constraining oncogene-driven transformation and suppressing somatic reprogramming efficiency.
In a separate collaborative study, I defined how another pseudouridine synthase, PUS7, modifies a stem-cell enriched subset of tdRs to regulate translation via interaction with PABPC1, with implications for haematopoiesis and leukaemogenesis.
Finally, I contributed to research uncovering a role for RNA demethylase ALKBH5 in modulating translation of the splicing factor SF3B1. This regulation directs splicing of DNA repair and epigenetic regulators during oncogenic transformation, ultimately influencing genome integrity and leukaemia progression in vivo.
Collectively, these studies reveal novel roles for RNA modifying enzymes in coordinating cellular responses to genotoxic, immune, and oncogenic stress, highlighting their importance in regulating translation, inflammation, genome stability, and cell plasticity across health and disease. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • PhD Kutter, Claudia, Department of Microbiology, Tumor and Cell Biology, Division of SciLife Regulatory Transcriptomics; KI
organization
publishing date
type
Thesis
publication status
published
subject
keywords
RNA, tRNA-derived small RNAs (tDRs), RNA modifications, pseudouridine, pseudouridine synthase (PUS), transposable elements (TEs), inflammation, autoimmune diseases, cancer, DNA damage response (DDR), haematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs)
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2025:105
pages
90 pages
publisher
Lund University, Faculty of Medicine
defense location
BMC I1345, Sölvegatan 19 i Lund. Join by Zoom: https://lu-se.zoom.us/j/61223834739?pwd=2Z1Qak3ldbebnL8NqeLcbomSoS1NWY.1
defense date
2025-09-20 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-758-3
language
English
LU publication?
yes
id
cf3b9950-c5a9-4efc-9fbb-f668d5aa99c9
date added to LUP
2025-08-28 14:28:43
date last changed
2025-09-09 11:30:01
@phdthesis{cf3b9950-c5a9-4efc-9fbb-f668d5aa99c9,
  abstract     = {{RNA modifying enzymes play a pivotal role in reshaping gene expression programs in response to diverse intracellular and extracellular cues, thereby maintaining cellular homeostasis. When dysregulated, these enzymes are increasingly implicated in the onset and progression of various diseases. While traditionally recognised for their catalytic functions, mounting evidence suggests that many RNA modifying enzymes exhibit additional non-catalytic “moonlighting” activities. However, the full extent of their multifunctionality remains poorly understood.<br/>In the first study, I defined a previously unrecognized role for pseudouridine synthase 10 (PUS10) in regulating the innate immune response. Using in vitro and in vivo model systems, I demonstrated that PUS10 deficiency leads to upregulation of interferon-stimulated genes (ISGs). Mechanistically, PUS10 utilizes a specific subset of tRNA-derived small RNAs (tdRs) to regulate translation and suppress the expression of endogenous retroelements. PUS10 loss triggers activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, likely via RNA-DNA hybrids accumulation. Furthermore, I uncovered a transcriptional signature associated with PUS10 that correlates with autoimmune disease. Together, these findings identify PUS10 as a novel regulator of viral mimicry and immune balance.<br/>Based on prior evidence, I discovered that PUS10 depletion affects DNA damage response (DDR) signalling pathways, sensitizes cells to DNA damage-induced cell death and disrupts cell cycle progression. PUS10 appears to influence DNA repair pathway choice by suppressing error-prone non-homologous end joining (NHEJ) and favouring high-fidelity homologous recombination (HR). Beyond genome maintenance, PUS10 modulates cell fate transitions by constraining oncogene-driven transformation and suppressing somatic reprogramming efficiency.<br/>In a separate collaborative study, I defined how another pseudouridine synthase, PUS7, modifies a stem-cell enriched subset of tdRs to regulate translation via interaction with PABPC1, with implications for haematopoiesis and leukaemogenesis.<br/>Finally, I contributed to research uncovering a role for RNA demethylase ALKBH5 in modulating translation of the splicing factor SF3B1. This regulation directs splicing of DNA repair and epigenetic regulators during oncogenic transformation, ultimately influencing genome integrity and leukaemia progression in vivo.<br/>Collectively, these studies reveal novel roles for RNA modifying enzymes in coordinating cellular responses to genotoxic, immune, and oncogenic stress, highlighting their importance in regulating translation, inflammation, genome stability, and cell plasticity across health and disease.}},
  author       = {{Madej, Magdalena}},
  isbn         = {{978-91-8021-758-3}},
  issn         = {{1652-8220}},
  keywords     = {{RNA; tRNA-derived small RNAs (tDRs); RNA modifications; pseudouridine; pseudouridine synthase (PUS); transposable elements (TEs); inflammation; autoimmune diseases; cancer; DNA damage response (DDR); haematopoietic stem cells (HSCs); induced pluripotent stem cells (iPSCs)}},
  language     = {{eng}},
  number       = {{2025:105}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Decoding the RNA regulome governing cellular stress responses and cell fate transitions}},
  url          = {{https://lup.lub.lu.se/search/files/226441659/MMadej_LUCRIS_e-nailing.pdf}},
  year         = {{2025}},
}