TDP-43 dysfunction results in R-loop accumulation and DNA replication defects
Abstract
TDP-43 is an RNA binding protein whose aggregation is a hallmark of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) 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 find 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 critical 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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jan 01, 2020
- Source ID
- 10.1242/jcs.244129
Entities
People
- Albert A Davis
- Alessandro Vindigni
- Annabel Quinet
- Matthew Wood
- Philippe Pasero
- Yea-lih Lin
- Yuna M Ayala
Organizations
- Alvin J. Siteman Cancer Center
- National Institutes of Health
- Saint Louis University
- United States Department of Defense
- University of Montpellier
- Washington University in St. Louis