TDP-43 dysfunction results in R-loop accumulation and DNA replication defects
Autor: | Wood, Matthew, Quinet, Annabel, Lin, Yea-Lih, Davis, Albert, Pasero, Philippe, Ayala, Yuna, Vindigni, Alessandro |
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Přispěvatelé: | Washington University in Saint Louis (WUSTL), Saint Louis University (SLU), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS) |
Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
DNA Replication
TDP-43 [SDV]Life Sciences [q-bio] Immunology MESH: RecQ Helicases MESH: Exodeoxyribonucleases MESH: DNA Helicases MESH: Terminator Regions Genetic MESH: DNA Replication Dermatology EXDL2 MESH: BRCA2 Protein mental disorders MESH: RNA Small Interfering EXD2 MESH: Neoplasms fork regression TARDBP MESH: BRCA1 Protein Adult stem cells RNA:DNA hybrids MESH: Humans MESH: R-Loop Structures MESH: Transcription Genetic MESH: Genomic Instability nutritional and metabolic diseases R-loops Cellular immune response BRCA1 BRCA2 nervous system diseases MESH: HeLa Cells MESH: Synthetic Lethal Mutations |
Zdroj: | Journal of Cell Science Journal of Cell Science, Company of Biologists, 2020, 133 (20), pp.jcs244129. ⟨10.1242/jcs.244129⟩ |
ISSN: | 0021-9533 1477-9137 |
Popis: | International audience; 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. |
Databáze: | OpenAIRE |
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