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TDP-43 dysfunction results in R-loop accumulation and DNA replication defects.

Authors
  • Wood, Matthew1, 2
  • Quinet, Annabel1
  • Lin, Yea-Lih3
  • Davis, Albert A4
  • Pasero, Philippe3
  • Ayala, Yuna M5
  • Vindigni, Alessandro6, 2
  • 1 Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 2 Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
  • 3 Institut de Génétique Humaine, CNRS et Université de Montpellier, Equipe labélisée Ligue contre le Cancer, Montpellier 34396, France. , (France)
  • 4 Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, USA.
  • 5 Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA [email protected] [email protected]
  • 6 Division of Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA [email protected] [email protected]
Type
Published Article
Journal
Journal of Cell Science
Publisher
The Company of Biologists
Publication Date
Oct 30, 2020
Volume
133
Issue
20
Identifiers
DOI: 10.1242/jcs.244129
PMID: 32989039
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

TAR DNA-binding protein 43 (TDP-43; also known as TARDBP) is an RNA-binding protein whose aggregation is a hallmark of the neurodegenerative disorders amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 loss increases DNA damage and compromises cell viability, but the actual function of TDP-43 in preventing genome instability remains unclear. Here, we show that loss of TDP-43 increases R-loop formation in a transcription-dependent manner and results in DNA replication stress. TDP-43 nucleic-acid-binding and self-assembly activities are important in inhibiting R-loop accumulation and preserving normal DNA replication. We also found that TDP-43 cytoplasmic aggregation impairs TDP-43 function in R-loop regulation. Furthermore, increased R-loop accumulation and DNA damage is observed in neurons upon loss of TDP-43. Together, our findings indicate that TDP-43 function and normal protein homeostasis are crucial in maintaining genomic stability through a co-transcriptional process that prevents aberrant R-loop accumulation. We propose that the increased R-loop formation and genomic instability associated with TDP-43 loss are linked to the pathogenesis of TDP-43 proteinopathies.This article has an associated First Person interview with the first author of the paper. © 2020. Published by The Company of Biologists Ltd.

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