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

Matthew Wood Annabel Quinet Albert Davis Yuna Ayala Alessandro Vindigni 1 Ismaël Padioleau 2 Yaqun Liu 3 Lionel Sanz 4 Anna Biernacka 5 Magdalena Skrzypczak 5 Maga Rowicka Krzysztof Ginalski Frédéric Chedin Chun-Long Chen F. Coquel M. Silva H. Técher K. Zadorozhny S. Sharma Clément Mettling E. Dardillac A. Barthe Anne-Lyne Schmitz Alexy Promonet A. Cribier Amélie Sarrazin B. Lopez V. Costanzo L. Krejci A. Chabes Cindy Orvain Francette Jean-Louis Hakim Hocini Barbara Hersant Yamina Bennasser Nicolas Ortonne Claire Hotz Pierre Wolkenstein Michele Boniotto Pascaline Tisserand Cécile Lefebvre Jean-Daniel Lelièvre Monsef Benkirane Yves Lévy Sophie Hüe Jadwiga Nieminuszczy Ronan Broderick Marina Bellani Elizabeth Smethurst Rebekka Schwab Veronica Cherdyntseva Theodora Evmorfopoulou Yea-Lih Lin Michal Minczuk Philippe Pasero Sarantis Gagos Michael Seidman Wojciech Niedzwiedz
1 Laboratorium für Festkörperphysik
2 IGH - Institut de génétique humaine
3 DIG CANCER - Dynamique de l'information génétique : bases fondamentales et cancer
4 IGMM - Institut de Génétique Moléculaire de Montpellier
5 Laboratory of Bioinformatics and Systems Biology, Centre of New Technologies, University of Warsaw, 02-089 Warsaw, Poland
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.
Keywords : DNA Replication R-loops RNA:DNA hybrids TARDBP TDP-43 Adult stem cells Cellular immune response Dermatology Immunology BRCA1 BRCA2 DNA replication EXD2 EXDL2 fork regression
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Journal articles
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https://hal-cnrs.archives-ouvertes.fr/hal-03078591
Contributor : Yea-Lih Lin <>
Submitted on : Wednesday, December 16, 2020 - 5:50:11 PM
Last modification on : Friday, December 18, 2020 - 11:36:04 AM

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CNRS | CURIE | PSL | FNCLCC | UNIV-MONTPELLIER | DIG_CANCER | BS | SU-SCIENCES | SORBONNE-UNIVERSITE | SU-TI

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Matthew Wood, Annabel Quinet, Albert Davis, Yuna Ayala, Alessandro Vindigni, 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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