TDP1 mutation causing SCAN1 neurodegenerative syndrome hampers the repair of transcriptional DNA double-strand breaks
Mathéa Geraud,
Agnese Cristini,
Simona Salimbeni,
Nicolas Bery,
Virginie Jouffret,
Marco Russo,
Andrea Carla Ajello,
Lara Fernandez Martinez,
Jessica Marinello,
Pierre Cordelier,
Didier Trouche,
Gilles Favre,
Estelle Nicolas,
Giovanni Capranico,
Olivier Sordet
Affiliations
Mathéa Geraud
Cancer Research Center of Toulouse (CRCT), INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, 31037 Toulouse, France
Agnese Cristini
Cancer Research Center of Toulouse (CRCT), INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, 31037 Toulouse, France
Simona Salimbeni
Cancer Research Center of Toulouse (CRCT), INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, 31037 Toulouse, France; Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy
Nicolas Bery
Cancer Research Center of Toulouse (CRCT), INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, 31037 Toulouse, France
Virginie Jouffret
MCD, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062 Toulouse, France; BigA Core Facility, Centre de Biologie Intégrative (CBI), Université de Toulouse, 31062 Toulouse, France
Marco Russo
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy
Andrea Carla Ajello
Cancer Research Center of Toulouse (CRCT), INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, 31037 Toulouse, France
Lara Fernandez Martinez
Cancer Research Center of Toulouse (CRCT), INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, 31037 Toulouse, France
Jessica Marinello
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy
Pierre Cordelier
Cancer Research Center of Toulouse (CRCT), INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, 31037 Toulouse, France
Didier Trouche
MCD, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062 Toulouse, France
Gilles Favre
Cancer Research Center of Toulouse (CRCT), INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, 31037 Toulouse, France
Estelle Nicolas
MCD, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062 Toulouse, France
Giovanni Capranico
Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; Corresponding author
Olivier Sordet
Cancer Research Center of Toulouse (CRCT), INSERM, Université de Toulouse, Université Toulouse III Paul Sabatier, CNRS, 31037 Toulouse, France; Corresponding author
Summary: TDP1 removes transcription-blocking topoisomerase I cleavage complexes (TOP1ccs), and its inactivating H493R mutation causes the neurodegenerative syndrome SCAN1. However, the molecular mechanism underlying the SCAN1 phenotype is unclear. Here, we generate human SCAN1 cell models using CRISPR-Cas9 and show that they accumulate TOP1ccs along with changes in gene expression and genomic distribution of R-loops. SCAN1 cells also accumulate transcriptional DNA double-strand breaks (DSBs) specifically in the G1 cell population due to increased DSB formation and lack of repair, both resulting from abortive removal of transcription-blocking TOP1ccs. Deficient TDP1 activity causes increased DSB production, and the presence of mutated TDP1 protein hampers DSB repair by a TDP2-dependent backup pathway. This study provides powerful models to study TDP1 functions under physiological and pathological conditions and unravels that a gain of function of the mutated TDP1 protein, which prevents DSB repair, rather than a loss of TDP1 activity itself, could contribute to SCAN1 pathogenesis.
