脆性X综合征是世界范围内最常见的遗传性智力缺陷，由脆性X智障蛋白（Fragile X mental retardation protein，FMRP）功能缺陷导致，但对其致病机制目前所知甚少。中国科学院遗传与发育生物学研究所张永清研究小组和大连医科大学肿瘤干细胞研究员秘晓林研究团队密切合作，发现了FMRP参与调节DNA损伤应答的机制。
利用经典的模式生物果蝇，研究人员发现突变体果蝇对γ-射线和化学诱变剂高度敏感。FMRP缺失果蝇呈现DNA损伤导致的G2/M细胞周期检验点缺陷，这种缺陷是由于FMRP缺失果蝇中细胞分裂素CycB的表达异常升高导致的。CycB是调节细胞进入有丝分裂期的关键因子之一，研究发现FMRP可以与CycB mRNA结合，抑制CycB蛋白的表达，从而参与对细胞周期的调节。此外，FMRP缺失果蝇表现出辐射导致的p53依赖性细胞凋亡显著增多。
本研究首次揭示FMRP蛋白参与DNA损伤应答，扩展了人们对DNA损伤应答机制的了解。同时，也加深了对脆性X综合症发病机理的认识，为脆性X综合征的诊断治疗提供了新的思路。
该研究结果于7月26日在线发表于Human Molecular Genetics杂志（DOI：10.1093/hmg/dds307），张永清实验室的刘威博士是论文第一作者。
该研究工作得到了国家自然科学基金委、科技部和中国科学院的资助。（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.
