A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia. - Archive ouverte HAL Access content directly
Journal Articles PLoS Biology Year : 2010

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

(1) , (1) , (1) , (2) , (3) , (1) , (1) , (2) , (1) , (1) , (4) , (3) , (5) , (3, 6) , (3) , (4) , (3, 6) , (1) , (2) , (3) , (1)
1
2
3
4
5
6

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.
Fichier principal
Vignette du fichier
journal.pbio.1000408.pdf (2.22 Mo) Télécharger le fichier
Origin : Publisher files allowed on an open archive
Loading...

Dates and versions

inserm-00707271 , version 1 (12-06-2012)

Identifiers

Cite

Mikołaj Słabicki, Mirko Theis, Dragomir B. 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, 2010, 8 (6), pp.e1000408. ⟨10.1371/journal.pbio.1000408⟩. ⟨inserm-00707271⟩
727 View
438 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More