A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
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.
Details
Original language | English |
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Article number | e1000408 |
Number of pages | 16 |
Journal | PLoS Biology |
Volume | 8 |
Issue number | 6 |
Publication status | Published - 29 Jun 2010 |
Peer-reviewed | Yes |
External IDs
Scopus | 77954706670 |
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PubMed | 20613862 |
PubMedCentral | PMC2893954 |
Keywords
Sustainable Development Goals
Keywords
- DNA Repair, Gene Knockdown Techniques, Genome, Human, Humans, RNA Interference, Recombination, Genetic, Spastic Paraplegia, Hereditary/genetics