德國研究人員在尋找參與修復(fù)脫氧核糖核酸（DNA）雙鏈斷裂的基因方面獲得進(jìn)展。研究小組在人類細(xì)胞中找到61個(gè)位點(diǎn),，并發(fā)現(xiàn)了此前未知的與DNA雙鏈斷裂修復(fù)有關(guān)的基因,。該研究結(jié)果將顯著加速DNA修復(fù)基因的繼續(xù)搜尋，并帶來新的醫(yī)療應(yīng)用可能,。相關(guān)研究成果發(fā)表在6月29日的《公共科學(xué)圖書館·生物學(xué)》雜志上,。
細(xì)胞中存在能重新快速修復(fù)遺傳信息載體損壞部分的特殊修復(fù)基因，當(dāng)這些基因失效時(shí),，往往會導(dǎo)致嚴(yán)重的疾病,。
德國馬克斯普朗克分子細(xì)胞生物學(xué)和遺傳學(xué)研究所的研究人員在弗蘭克·布赫霍爾茨的領(lǐng)導(dǎo)下，在基因組廣泛掃描中有目的地尋找那些參與修復(fù)DNA雙鏈斷裂的基因,，在人類細(xì)胞中找出61個(gè)位點(diǎn),，并且發(fā)現(xiàn)了與DNA雙鏈斷裂修復(fù)相關(guān)的新基因KIAA0415。該基因如果被關(guān)閉,，將降低細(xì)胞修復(fù)DNA斷裂的能力,。對該基因的研究顯示，它與導(dǎo)致遺傳性痙攣性截癱（HSP）的突變基因有相互作用,。HSP是具有高度臨床變異性和遺傳異質(zhì)性的神經(jīng)系統(tǒng)遺傳病,，癥狀是慢性行進(jìn)無力與慢性痙攣性下肢癱瘓。提示：生物谷新域名www.bioon.net
德累斯頓研究團(tuán)隊(duì)推斷,，或許是基因KIAA0415的突變引發(fā)了HSP這種疾病,。他們通過與法國國家健康和醫(yī)學(xué)研究院（INSERM）的醫(yī)療小組合作，在HSP患者身上發(fā)現(xiàn)了KIAA0415基因的突變,，與SPG11和SPG15共同起作用的SPG48中存在KIAA0415基因,。研究人員進(jìn)一步觀察后發(fā)現(xiàn)，當(dāng)SPG48不起作用時(shí),，破壞DNA的物質(zhì)更容易得逞,。
布赫霍爾茨表示，當(dāng)SPG48因?yàn)樽儺惗还ぷ鲿r(shí),，DNA雙鏈斷裂的修復(fù)也會因此失效,，相應(yīng)細(xì)胞將最終失去活性并死亡。這不僅論證了SPG48基因是DNA修復(fù)運(yùn)作的前提,，還說明了DNA修復(fù)與疾病之間的關(guān)聯(lián),。(生物谷Bioon.net)
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生物谷推薦原文出處：
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.
