A Genome-Scale DNA Repair RNAi Screen Identifies SPG48 as a Novel Gene Associated with Hereditary Spastic Paraplegia

Mikołaj Słabicki, Mirko Theis, Dragomir B. Krastev, Sergey Samsonov, Emeline Mundwiller, Magno Junqueira, Maciej Paszkowski-Rogacz, Joan Teyra, Anne-Kristin Heninger, Ina Poser, Fabienne Prieur, Jérémy Truchetto, Christian Confavreux, Cécilia Marelli, Alexandra Durr, Jean Philippe Camdessanche, Alexis Brice, Andrej Shevchenko, M. Teresa Pisabarro, Giovanni Stevanin, Frank Buchholz
PLoS Biol. 2010-06-29; 8(6): e1000408
DOI: 10.1371/JOURNAL.PBIO.1000408

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1. PLoS Biol. 2010 Jun 29;8(6):e1000408. doi: 10.1371/journal.pbio.1000408.

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

Słabicki M(1), 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.

Author information:
(1)Max Planck Institute for Molecular Cell Biology and Genetics, Dresden,

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.

DOI: 10.1371/journal.pbio.1000408
PMCID: PMC2893954
PMID: 20613862 [Indexed for MEDLINE]

Conflict of interest statement: The authors have declared that no competing
interests exist.

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