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

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.
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https://hal-cnrs.archives-ouvertes.fr/hal-03078591
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Submitted on : Thursday, June 10, 2021 - 5:10:26 PM
Last modification on : Monday, October 11, 2021 - 1:22:29 PM
Long-term archiving on: : Saturday, September 11, 2021 - 7:30:07 PM

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Matthew Wood, Annabel Quinet, Yea-Lih Lin, Albert Davis, Philippe Pasero, et al.. TDP-43 dysfunction results in R-loop accumulation and DNA replication defects. Journal of Cell Science, Company of Biologists, 2020, 133 (20), pp.jcs244129. ⟨10.1242/jcs.244129⟩. ⟨hal-03078591⟩

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