New HSP gene discovered

Posted - July 2010 in Research Highlights

Link between HSP and DNA repair

The discovery that a protein complex required for DNA repair is mutated in HSP patients suggests a link between HSP and DNA repair.

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 HSP patients suggests a link between HSP and DNA repair.

SOURCE: PLoS Biol. 2010 Jun 29;8(6):e1000408.

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

Słabicki M, Theis M, Krastev DB, Samsonov S, Mundwiller E, Junqueira M, Paszkowski-Rogacz M, Teyra J, Heninger AK, Poser I, Prieur F, Truchetto J, Confavreux C, Marelli C, Durr A, Camdessanche JP, Brice A, Shevchenko A, Pisabarro MT, Stevanin G, Buchholz F.

Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany.

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