Xrp1 governs the stress response program to spliceosome dysfunction DOI Creative Commons
Dimitrije Stanković, Luke S. Tain, Mirka Uhlířová

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(5), P. 2093 - 2111

Published: Feb. 2, 2024

Abstract Co-transcriptional processing of nascent pre-mRNAs by the spliceosome is vital to regulating gene expression and maintaining genome integrity. Here, we show that deficiency functional U5 small nuclear ribonucleoprotein particles (snRNPs) in Drosophila imaginal cells causes extensive transcriptome remodeling accumulation highly mutagenic R-loops, triggering a robust stress response cell cycle arrest. Despite compromised proliferative capacity, snRNP-deficient increased protein translation size, causing intra-organ growth disbalance before being gradually eliminated via apoptosis. We identify Xrp1-Irbp18 heterodimer as primary driver transcriptional cellular program downstream snRNP malfunction. Knockdown Xrp1 or Irbp18 attenuated JNK p53 activity, restored normal progression growth, inhibited death. Reducing Xrp1-Irbp18, however, did not rescue splicing defects, highlighting requirement accurate for tissue homeostasis. Our work provides novel insights into crosstalk between DNA damage defines critical sensor malfunction mediator stress-induced senescence program.

Language: Английский

Cell competition in development, homeostasis and cancer DOI
Sanne M. van Neerven, Louis Vermeulen

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(3), P. 221 - 236

Published: Sept. 29, 2022

Language: Английский

Citations

81
Ribosome biogenesis and the cellular energy economy DOI Creative Commons
David Shore, Benjamin Albert

Current Biology, Journal Year: 2022, Volume and Issue: 32(12), P. R611 - R617

Published: June 1, 2022

Language: Английский

Citations

76
Transcriptional control of ribosome biogenesis in yeast: links to growth and stress signals DOI Creative Commons
David Shore, Sevil Zencir, Benjamin Albert

et al.

Biochemical Society Transactions, Journal Year: 2021, Volume and Issue: 49(4), P. 1589 - 1599

Published: July 9, 2021

Ribosome biogenesis requires prodigious transcriptional output in rapidly growing yeast cells and is highly regulated response to both growth stress signals. This minireview focuses on recent developments our understanding of this regulatory process, with an emphasis the 138 ribosomal protein genes (RPGs) themselves a group >200 ribosome (RiBi) whose products contribute assembly but are not part ribosome. Expression most RPGs depends upon Rap1, pioneer transcription factor (TF) required for binding pair RPG-specific TFs called Fhl1 Ifh1. RPG expression correlated Ifh1 promoter binding, whereas Rap1 remain promoter-associated stress-induced down regulation. A TF Sfp1 has also been implicated regulation, though work reveals that its primary function activation RiBi other growth-related genes. plays important role at small number where Rap1-Fhl1-Ifh1 action subsidiary or non-existent. In addition, nearly half all bound by Hmo1, which either stabilizes re-configures Fhl1-Ifh1 binding. Recent studies identified proline rotamase Fpr1, known primarily rapamycin-mediated inhibition TORC1 kinase, as additional promoters. Fpr1 affects independently cooperation Hmo1. Finally, major development was discovery homeostasis mechanism driven unassembled proteins, referred Assembly Stress Response (RASTR), controls through reversible condensation

Language: Английский

Citations

67
Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition DOI
Carles Recasens-Alvarez,

Cyrille Alexandre,

Joanna Kirkpatrick

et al.

Nature Cell Biology, Journal Year: 2021, Volume and Issue: 23(2), P. 127 - 135

Published: Jan. 25, 2021

Language: Английский

Citations

63
The homeostatic regulation of ribosome biogenesis DOI Creative Commons
Chunyang Ni, Michael Buszczak

Seminars in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 136, P. 13 - 26

Published: April 16, 2022

Language: Английский

Citations

44
The transcription factor Xrp1 is required for PERK-mediated antioxidant gene induction in Drosophila DOI Creative Commons
Brian Brown, Sahana Mitra, F. Roach

et al.

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Oct. 4, 2021

PERK is an endoplasmic reticulum (ER) transmembrane sensor that phosphorylates eIF2α to initiate the Unfolded Protein Response (UPR). phosphorylation promotes stress-responsive gene expression most notably through transcription factor ATF4 contains a regulatory 5' leader. Possible effectors other than remain poorly understood. Here, we report bZIP Xrp1 required for ATF4-independent signaling. Cell-type-specific profiling in Drosophila indicated delta-family glutathione-S-transferases (gstD) are prominently induced by UPR-activating transgene Rh1G69D. Perk was necessary and sufficient such gstD induction, but not required. Instead, regulators of regulated protein levels induce gstDs. The leader has conserved upstream Open Reading Frame (uORF) analogous those regulate translation. gstD-GFP reporter induction putative binding sites. These results indicate antioxidant genes highly previously unrecognized UPR signaling axis consisting Xrp1.

Language: Английский

Citations

42
Shared enhancer gene regulatory networks between wound and oncogenic programs DOI Creative Commons
Swann Floc’hlay,

Ramya Balaji,

Dimitrije Stanković

et al.

eLife, Journal Year: 2023, Volume and Issue: 12

Published: May 3, 2023

Wound response programs are often activated during neoplastic growth in tumors. In both wound repair and tumor growth, cells respond to acute stress balance the activation of multiple programs, including apoptosis, proliferation, cell migration. Central those responses JNK/MAPK JAK/STAT signaling pathways. Yet, what extent these cascades interact at cis-regulatory level how they orchestrate different regulatory phenotypic is still unclear. Here, we aim characterize states that emerge cooperate response, using Drosophila melanogaster wing disc as a model system, compare with cancer induced by rasV12scrib-/- eye disc. We used single-cell multiome profiling derive enhancer gene networks (eGRNs) integrating chromatin accessibility expression signals. identify 'proliferative' eGRN, active majority wounded controlled AP-1 STAT. smaller, but distinct population cells, 'senescent' eGRN driven C/EBP-like transcription factors (Irbp18, Xrp1, Slow border, Vrille) Scalloped. These two signatures found be levels. Our eGRNs resource offers an in-depth characterization senescence markers, together new perspective on shared acting oncogenesis.

Language: Английский

Citations

17
Cell competition and cancer from Drosophila to mammals DOI Creative Commons
Bojie Cong, Ross Cagan

Oncogenesis, Journal Year: 2024, Volume and Issue: 13(1)

Published: Jan. 3, 2024

Abstract Throughout an individual’s life, somatic cells acquire cancer-associated mutations. A fraction of these mutations trigger tumour formation, a phenomenon partly driven by the interplay mutant and wild-type cell clones competing for dominance; conversely, other function against initiation. This mechanism ‘cell competition’, can shift clone dynamics evaluating relative status clonal populations, promoting ‘winners’ eliminating ‘losers’. review examines role competition in context tumorigenesis, progression therapeutic intervention.

Language: Английский

Citations

8
Cell competition: emerging signaling and unsolved questions DOI Creative Commons
Rina Nagata, Tatsushi Igaki

FEBS Letters, Journal Year: 2024, Volume and Issue: 598(4), P. 379 - 389

Published: Feb. 1, 2024

Multicellular communities have an intrinsic mechanism that optimizes their structure and function via cell–cell communication. One of the driving forces for such self‐organization multicellular system is cell competition, elimination viable unfit or deleterious cells interaction. Studies in Drosophila mammals identified multiple mechanisms competition caused by different types mutations cellular changes. Intriguingly, recent studies found “losers” commonly show reduced protein synthesis. In , reduction synthesis levels loser phosphorylation translation initiation factor eIF2α a bZip transcription Xrp1. Given variety stresses converge on thus global inhibition synthesis, may be machinery fitness removing stressed cells. this review, we summarize discuss emerging signaling critical unsolved questions, as well role competition.

Language: Английский

Citations

7
ER stress and the unfolded protein response in gastrointestinal stem cells and carcinogenesis DOI
Ruben J. de Boer,

Jooske F. van Lidth de Jeude,

Jarom Heijmans

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: 587, P. 216678 - 216678

Published: Feb. 14, 2024

Language: Английский

Citations

7