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Sci Rep. 2019 Jan 24;9(1):651. doi: 10.1038/s41598-018-36912-0.

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

Author information

1
Department of Research, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Via Amadeo 42, 20133, Milano, Italy.
2
Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133, Milano, Italy.
3
Universita' degli Studi di Torino, Bioinformatics and Genomics Unit, Molecular Biotechnology Centre, Via Nizza 52, 10126, Torino, Italy.
4
Fondazione IRCCS Istituto Neurologico Carlo Besta, Department of Neurophysiopathology and Diagnostic Epileptology, Via Celoria 11, 20133, Milano, Italy.
5
Institute of Molecular and Cellular Pharmacology (IPMC) LabEx ICST, CNRS UMR7275, Route des Lucioles, 06560, Valbonne, Sophia Antipolis, France.
6
University Côte d'Azur, 660 Route des Lucioles, 06560, Valbonne, Sophia Antipolis, France.
7
Department of Research, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133, Milano, Italy.
8
Department of Research, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Via G Venezian 1, 20133, Milano, Italy.
9
Department of Medical Genetics, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warsaw, Poland.
10
Department of Research, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Via Amadeo 42, 20133, Milano, Italy. domenico.delia@ifom.eu.
11
IFOM, FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milano, Italy. domenico.delia@ifom.eu.

Abstract

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.

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