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

Matthew Wood, Annabel Quinet, Yea Lih Lin, Albert A. Davis, Philippe Pasero, Yuna M. Ayala, Alessandro Vindigni

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish
Article numberjcs244129
JournalJournal of cell science
Volume133
Issue number20
DOIs
StatePublished - Oct 2020

Keywords

  • DNA Replication
  • R-loops
  • RNA:DNA hybrids
  • TARDBP
  • TDP-43

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