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A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia.

Mikołaj Słabicki 1 Mirko Theis 1 Dragomir Krastev 1 Sergey Samsonov 2 Emeline Mundwiller 3 Magno Junqueira 1 Maciej Paszkowski-Rogacz 1 Joan Teyra 2 Anne-Kristin Heninger 1 Ina Poser 1 Fabienne Prieur 4 Jérémy Truchetto 3 Christian Confavreux 5 Cécilia Marelli 3, 6 Alexandra Durr 3 Jean Philippe Camdessanche 4 Alexis Brice 3, 6 Andrej Shevchenko 1 M Teresa Pisabarro 2 Giovanni Stevanin 3 Frank Buchholz 1, *
* Corresponding author
1 MPI-CBG - Max Planck Institute of Molecular Cell Biology and Genetics
2 Structural Bioinformatics
3 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
4 Service de Génétique Clinique Chromosomique et Moléculaire
5 Hôpital neurologique
6 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
Abstract : DNA repair is essential to maintain genome integrity, and genes with roles in DNA repair are frequently mutated in a variety of human diseases. Repair via homologous recombination typically restores the original DNA sequence without introducing mutations, and a number of genes that are required for homologous recombination DNA double-strand break repair (HR-DSBR) have been identified. However, a systematic analysis of this important DNA repair pathway in mammalian cells has not been reported. Here, we describe a genome-scale endoribonuclease-prepared short interfering RNA (esiRNA) screen for genes involved in DNA double strand break repair. We report 61 genes that influenced the frequency of HR-DSBR and characterize in detail one of the genes that decreased the frequency of HR-DSBR. We show that the gene KIAA0415 encodes a putative helicase that interacts with SPG11 and SPG15, two proteins mutated in hereditary spastic paraplegia (HSP). We identify mutations in HSP patients, discovering KIAA0415/SPG48 as a novel HSP-associated gene, and show that a KIAA0415/SPG48 mutant cell line is more sensitive to DNA damaging drugs. We present the first genome-scale survey of HR-DSBR in mammalian cells providing a dataset that should accelerate the discovery of novel genes with roles in DNA repair and associated medical conditions. The discovery that proteins forming a novel protein complex are required for efficient HR-DSBR and are mutated in patients suffering from HSP suggests a link between HSP and DNA repair.
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Mikołaj Słabicki, Mirko Theis, Dragomir Krastev, Sergey Samsonov, Emeline Mundwiller, et al.. A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia.. PLoS Biology, Public Library of Science, 2010, 8 (6), pp.e1000408. ⟨10.1371/journal.pbio.1000408⟩. ⟨inserm-00707271⟩

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