脆性X綜合征是世界范圍內(nèi)最常見的遺傳性智力缺陷，由脆性X智障蛋白（Fragile X mental retardation protein,，F(xiàn)MRP）功能缺陷導(dǎo)致,，但對其致病機制目前所知甚少。中國科學院遺傳與發(fā)育生物學研究所張永清研究小組和大連醫(yī)科大學腫瘤干細胞研究員秘曉林研究團隊密切合作,，發(fā)現(xiàn)了FMRP參與調(diào)節(jié)DNA損傷應(yīng)答的機制,。
利用經(jīng)典的模式生物果蠅，研究人員發(fā)現(xiàn)突變體果蠅對γ-射線和化學誘變劑高度敏感,。FMRP缺失果蠅呈現(xiàn)DNA損傷導(dǎo)致的G2/M細胞周期檢驗點缺陷,，這種缺陷是由于FMRP缺失果蠅中細胞分裂素CycB的表達異常升高導(dǎo)致的。CycB是調(diào)節(jié)細胞進入有絲分裂期的關(guān)鍵因子之一,，研究發(fā)現(xiàn)FMRP可以與CycB mRNA結(jié)合,，抑制CycB蛋白的表達，從而參與對細胞周期的調(diào)節(jié),。此外,，F(xiàn)MRP缺失果蠅表現(xiàn)出輻射導(dǎo)致的p53依賴性細胞凋亡顯著增多。
本研究首次揭示FMRP蛋白參與DNA損傷應(yīng)答,，擴展了人們對DNA損傷應(yīng)答機制的了解,。同時，也加深了對脆性X綜合癥發(fā)病機理的認識,，為脆性X綜合征的診斷治療提供了新的思路,。
該研究結(jié)果于7月26日在線發(fā)表于Human Molecular Genetics雜志（DOI：10.1093/hmg/dds307），張永清實驗室的劉威博士是論文第一作者,。
該研究工作得到了國家自然科學基金委,、科技部和中國科學院的資助。（生物谷Bioon.com)
doi：10.1093/hmg/dds307
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Drosophila FMRP participates in the DNA damage response by regulating G2/M cell cycle checkpoint and apoptosis
Abstract
Fragile X syndrome (FXS),， the most common form of inherited mental retardation,， is caused by the loss of the fragile X mental retardation protein (FMRP). FMRP is a ubiquitously expressed， multi-domain RNA binding protein,， but its in vivo function remains poorly understood. Recent studies have shown that FMRP participates in cell cycle control during development. Here we used Drosophila mutants to test if FMRP plays a role in DNA damage response under genotoxic stress. We found significantly fewer dfmr1 mutants survived to adulthood than wild types following irradiation or exposure to chemical mutagens,， demonstrating that loss of dFMRP results in hypersensitivity to genotoxic stress. Genotoxic stress significantly reduced mitotic cells in wild-type brains， indicating activation of a DNA damage-induced G2/M checkpoint,， while mitosis was only moderately suppressed in dfmr1 mutants. Elevated expression of cyclin B,， a protein critical for the G2 to M transition,， was observed in the larval brains of dfmr1 mutants. CycB mRNA transcripts were enriched in the dFMRP-containing complex， suggesting that dFMRP regulates DNA damage induced G2/M checkpoint by repressing CycB mRNA translation. Reducing CycB dose by half in dfmr1 mutants rescued the defective G2/M checkpoint and reversed hypersensitivity to genotoxic stress. In addition,， dfmr1 mutants exhibited more DNA breaks and elevated p53-dependent apoptosis following irradiation. Moreover,， a loss-of-heterozygosity assay showed decreased irradiation-induced genome stability in dfmr1 mutants. Thus， dFMRP maintains genome stability under genotoxic stress and regulates the G2/M DNA damage checkpoint by suppressing CycB expression.
