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TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage

Marta Gianini, Daisy Sproviero, Aleix Bayona-Feliu, View ORCID ProfileCristina Cereda, View ORCID ProfileAndrés Aguilera
doi: https://doi.org/10.1101/2020.05.10.086652
Marta Gianini
1Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy
2Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
3Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Seville, Spain
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Daisy Sproviero
1Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy
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Aleix Bayona-Feliu
3Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Seville, Spain
4Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Seville, Spain
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Cristina Cereda
1Genomic and Post-Genomic Center, IRCCS Mondino Foundation, Pavia, Italy
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  • For correspondence: cristina.cereda@mondino.it aguilo@us.es
Andrés Aguilera
3Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Universidad de Sevilla-CSIC-Universidad Pablo de Olavide, Seville, Spain
4Departamento de Genética, Facultad de Biología, Universidad de Sevilla, Seville, Spain
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  • For correspondence: cristina.cereda@mondino.it aguilo@us.es
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Abstract

TDP-43 is a DNA and RNA binding protein involved in RNA processing and with structural resemblance to heterogeneous ribonucleoproteins (hnRNPs), whose depletion sensitizes neurons to double strand DNA breaks (DSBs). Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, in which 97% of patients are familial and sporadic cases associated with TDP-43 proteinopathies and conditions clearing TDP-43 from the nucleus, but we know little about the molecular basis of the disease. Here, we prove that mislocalization of mutated TDP-43 (A382T) in transfected neuronal SH-SY5Y and lymphoblastoid cell lines (LCLs) from an ALS patient cause R-loop accumulation, and R loop-dependent increased DSBs and Fanconi Anemia repair centers. Similar results were observed in a non-neuronal model of HeLa cells depleted of TDP-43. These results uncover a new role of TDP-43 in the control of co-transcriptional R-loops and the maintenance of genome integrity by preventing harmful R-loop accumulation. Our findings thus link TDP-43 pathology to increased R-loops and R loop-mediated DNA damage opening the possibility that R-loop modulation in TDP-43-defective cells might help develop ALS therapies.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 10, 2020.
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TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage
Marta Gianini, Daisy Sproviero, Aleix Bayona-Feliu, Cristina Cereda, Andrés Aguilera
bioRxiv 2020.05.10.086652; doi: https://doi.org/10.1101/2020.05.10.086652
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TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage
Marta Gianini, Daisy Sproviero, Aleix Bayona-Feliu, Cristina Cereda, Andrés Aguilera
bioRxiv 2020.05.10.086652; doi: https://doi.org/10.1101/2020.05.10.086652

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