德国研究人员在寻找参与修复脱氧核糖核酸（DNA）双链断裂的基因方面获得进展。研究小组在人类细胞中找到61个位点，并发现了此前未知的与DNA双链断裂修复有关的基因。该研究结果将显着加速DNA修复基因的继续搜寻，并带来新的医疗应用可能。相关研究成果发表在6月29日的《公共科学图书馆·生物学》杂志上。
细胞中存在能重新快速修复遗传信息载体损坏部分的特殊修复基因，当这些基因失效时，往往会导致严重的疾病。
德国马克斯普朗克分子细胞生物学和遗传学研究所的研究人员在弗兰克·布赫霍尔茨的领导下，在基因组广泛扫描中有目的地寻找那些参与修复DNA双链断裂的基因，在人类细胞中找出61个位点，并且发现了与DNA双链断裂修复相关的新基因KIAA0415。该基因如果被关闭，将降低细胞修复DNA断裂的能力。对该基因的研究显示，它与导致遗传性痉挛性截瘫（HSP）的突变基因有相互作用。HSP是具有高度临床变异性和遗传异质性的神经系统遗传病，症状是慢性行进无力与慢性痉挛性下肢瘫痪。提示：生物谷新域名www.bioon.net
德累斯顿研究团队推断，或许是基因KIAA0415的突变引发了HSP这种疾病。他们通过与法国国家健康和医学研究院（INSERM）的医疗小组合作，在HSP患者身上发现了KIAA0415基因的突变，与SPG11和SPG15共同起作用的SPG48中存在KIAA0415基因。研究人员进一步观察后发现，当SPG48不起作用时，破坏DNA的物质更容易得逞。
布赫霍尔茨表示，当SPG48因为变异而不工作时，DNA双链断裂的修复也会因此失效，相应细胞将最终失去活性并死亡。这不仅论证了SPG48基因是DNA修复运作的前提，还说明了DNA修复与疾病之间的关联。(生物谷Bioon.net)
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生物谷推荐原文出处：
PLoS Biology doi:10.1371/journal.pbio.1000408
A Genome-Scale DNA Repair RNAi Screen Identifies SPG48 as a Novel Gene Associated with Hereditary Spastic Paraplegia
Miko?aj S?abicki1, Mirko Theis1, Dragomir B. Krastev1, Sergey Samsonov2, Emeline Mundwiller3,4,5, Magno Junqueira1, Maciej Paszkowski-Rogacz1, Joan Teyra2, Anne-Kristin Heninger1, Ina Poser1, Fabienne Prieur6, Jérémy Truchetto3,4,5, Christian Confavreux7, Cécilia Marelli3,4,5,8, Alexandra Durr3,4,5,8, Jean Philippe Camdessanche6, Alexis Brice3,4,5,8, Andrej Shevchenko1, M. Teresa Pisabarro2, Giovanni Stevanin3,4,5,8, Frank Buchholz1*
1 Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany, 2 Structural Bioinformatics, BIOTEC TU, Dresden, Germany, 3 INSERM, Unit 975 Paris, France, 4 Université Pierre et Marie Curie-Paris6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Paris, France, 5 CNRS, Unité Mixte de Recherche 7225 Paris, France, 6 H?pital Nord, Saint Etienne, France, 7 H?pital Neurologique, Lyon, France, 8 APHP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France
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.
