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Article Dans Une Revue Scientific Reports Année : 2019

DNA damage and transcriptional regulation in iPSC-derived neurons from Ataxia Telangiectasia patients

DNA damage and transcriptional regulation in iPSC-derived neurons from Ataxia Telangiectasia patients.

Alessandro Corti
  • Fonction : Auteur
Raina Sota
  • Fonction : Auteur
Matteo Dugo
  • Fonction : Auteur
Michela Restelli
  • Fonction : Auteur
Daniele Lecis
  • Fonction : Auteur
Krystyna Chrzanowska
  • Fonction : Auteur
Domenico Delia
  • Fonction : Auteur

Résumé

Ataxia Telangiectasia (A-T) is neurodegenerative syndrome caused by inherited mutations inactivating the ATM kinase, a master regulator of the DNA damage response (DDR). What makes neurons vulnerable to ATM loss remains unclear. In this study we assessed on human iPSC-derived neurons whether the abnormal accumulation of DNA-Topoisomerase 1 adducts (Top1ccs) found in A-T impairs transcription elongation, thus favoring neurodegeneration. Furthermore, whether neuronal activity-induced immediate early genes (IEGs), a process involving the formation of DNA breaks, is affected by ATM deficiency. We found that Top1cc trapping by CPT induces an ATM-dependent DDR as well as an ATM-independent induction of IEGs and repression especially of long genes. As revealed by nascent RNA sequencing, transcriptional elongation and recovery were found to proceed with the same rate, irrespective of gene length and ATM status. Neuronal activity induced by glutamate receptors stimulation, or membrane depolarization with KCl, triggered a DDR and expression of IEGs, the latter independent of ATM. In unperturbed A-T neurons a set of genes (FN1, DCN, RASGRF1, FZD1, EOMES, SHH, NR2E1) implicated in the development, maintenance and physiology of central nervous system was specifically downregulated, underscoring their potential involvement in the neurodegenerative process in A-T patients.

Dates et versions

hal-02560558 , version 1 (02-05-2020)

Identifiants

Citer

Alessandro Corti, Raina Sota, Matteo Dugo, Raffaele Calogero, Benedetta Terragni, et al.. DNA damage and transcriptional regulation in iPSC-derived neurons from Ataxia Telangiectasia patients. Scientific Reports, 2019, 9 (1), pp.1-13. ⟨10.1038/s41598-018-36912-0⟩. ⟨hal-02560558⟩
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