中國(guó)科學(xué)院遺傳與發(fā)育生物學(xué)研究所楊崇林實(shí)驗(yàn)室以秀麗線蟲為模式,，探索蛋白質(zhì)精氨酸甲基化這一重要的蛋白質(zhì)翻譯后修飾方式在調(diào)控DNA損傷誘導(dǎo)的細(xì)胞凋亡方面的作用機(jī)制。
通過(guò)研究發(fā)現(xiàn)哺乳動(dòng)物II型蛋白質(zhì)精氨酸甲基轉(zhuǎn)移酶PRMT5在線蟲中的同源物,，即線蟲的PRMT-5,，參與調(diào)控DNA損傷引起的細(xì)胞凋亡。在prmt-5基因缺失的突變體中,，DNA損傷可誘導(dǎo)過(guò)量的細(xì)胞凋亡,。這一過(guò)量細(xì)胞凋亡緣于依賴于轉(zhuǎn)錄因子CEP-1(線蟲中腫瘤抑制因子p53的同源物)的凋亡起始因子EGL-1(促凋亡因子Puma和Noxa等的同源因子)的表達(dá)上調(diào)。該研究進(jìn)一步發(fā)現(xiàn)哺乳動(dòng)物細(xì)胞的轉(zhuǎn)錄協(xié)助因子p300在線蟲中的同源蛋白CBP-1也參與了prm-5突變體中egl-1的過(guò)量表達(dá),。蛋白質(zhì)互作分析發(fā)現(xiàn)PRMT-5可與CEP-1和CBP-1形成復(fù)合體,，并能夠甲基化修飾CBP-1。因此PRMT-5可能通過(guò)CBP-1對(duì)CEP-1的轉(zhuǎn)錄活性進(jìn)行負(fù)調(diào)控, 從而使有機(jī)體避免在DNA損傷后發(fā)生過(guò)量細(xì)胞凋亡,。前人發(fā)現(xiàn)PRMT5在多種腫瘤細(xì)胞中表達(dá)量增高,，但其與腫瘤發(fā)生之間的因果關(guān)系還甚為模糊。因此,，這一研究結(jié)果將為人們深入了解蛋白質(zhì)精氨酸甲基轉(zhuǎn)移酶在腫瘤發(fā)生中的作用機(jī)制提供新的思路,。
該研究結(jié)果在線發(fā)表于6月12日的PLoS Genetics雜志上，該實(shí)驗(yàn)室在讀博士生楊玫,、孫建偉為本論文的共同第一作者,。（生物谷Bioon.com）
生物谷推薦原始出處：
PLoS Genet 5(6): e1000514. doi:10.1371/journal.pgen.1000514
Caenorhabditis elegans Protein Arginine Methyltransferase PRMT-5 Negatively Regulates DNA Damage-Induced Apoptosis
Mei Yang1,2#, Jianwei Sun1,2#, Xiaojuan Sun1,2, Qinfang Shen1,2, Zhiyang Gao1, Chonglin Yang1*
1 Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China, 2 Graduate School, Chinese Academy of Sciences, Beijing, China
Arginine methylation of histone and non-histone proteins is involved in transcription regulation and many other cellular processes. Nevertheless, whether such protein modification plays a regulatory role during apoptosis remains largely unknown. Here we report that the Caenorhabditis elegans homolog of mammalian type II arginine methyltransferase PRMT5 negatively regulates DNA damage-induced apoptosis. We show that inactivation of C. elegans prmt-5 leads to excessive apoptosis in germline following ionizing irradiation, which is due to a CEP-1/p53–dependent up-regulation of the cell death initiator EGL-1. Moreover, we provide evidence that CBP-1, the worm ortholog of human p300/CBP, functions as a cofactor of CEP-1. PRMT-5 forms a complex with both CEP-1 and CBP-1 and can methylate the latter. Importantly, down-regulation of cbp-1 significantly suppresses DNA damage-induced egl-1 expression and apoptosis in prmt-5 mutant worms. These findings suggest that PRMT-5 likely represses CEP-1 transcriptional activity through CBP-1, which represents a novel regulatory mechanism of p53-dependent apoptosis.
