title: A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia.
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.
authors.affiliation: Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Mikołaj
authors.initials: M
authors.lastname: Słabicki
authors.forename: Mirko
authors.initials: M
authors.lastname: Theis
authors.forename: Dragomir B
authors.initials: DB
authors.lastname: Krastev
authors.forename: Sergey
authors.initials: S
authors.lastname: Samsonov
authors.forename: Emeline
authors.initials: E
authors.lastname: Mundwiller
authors.forename: Magno
authors.initials: M
authors.lastname: Junqueira
authors.forename: Maciej
authors.initials: M
authors.lastname: Paszkowski-Rogacz
authors.forename: Joan
authors.initials: J
authors.lastname: Teyra
authors.forename: Anne-Kristin
authors.initials: AK
authors.lastname: Heninger
authors.forename: Ina
authors.initials: I
authors.lastname: Poser
authors.forename: Fabienne
authors.initials: F
authors.lastname: Prieur
authors.forename: Jérémy
authors.initials: J
authors.lastname: Truchetto
authors.forename: Christian
authors.initials: C
authors.lastname: Confavreux
authors.forename: Cécilia
authors.initials: C
authors.lastname: Marelli
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.forename: Jean Philippe
authors.initials: JP
authors.lastname: Camdessanche
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Andrej
authors.initials: A
authors.lastname: Shevchenko
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Pisabarro
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Frank
authors.initials: F
authors.lastname: Buchholz
mesh_terms: D004260:DNA Repair; D055785:Gene Knockdown Techniques; D015894:Genome, Human; D006801:Humans; D034622:RNA Interference; D011995:Recombination, Genetic; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*