中国科学院遗传与发育生物学研究所杨崇林实验室以秀丽线虫为模式，探索蛋白质精氨酸甲基化这一重要的蛋白质翻译后修饰方式在调控DNA损伤诱导的细胞凋亡方面的作用机制。
通过研究发现哺乳动物II型蛋白质精氨酸甲基转移酶PRMT5在线虫中的同源物，即线虫的PRMT-5，参与调控DNA损伤引起的细胞凋亡。在prmt-5基因缺失的突变体中，DNA损伤可诱导过量的细胞凋亡。这一过量细胞凋亡缘于依赖于转录因子CEP-1(线虫中肿瘤抑制因子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)的表达上调。该研究进一步发现哺乳动物细胞的转录协助因子p300在线虫中的同源蛋白CBP-1也参与了prm-5突变体中egl-1的过量表达。蛋白质互作分析发现PRMT-5可与CEP-1和CBP-1形成复合体，并能够甲基化修饰CBP-1。因此PRMT-5可能通过CBP-1对CEP-1的转录活性进行负调控, 从而使有机体避免在DNA损伤后发生过量细胞凋亡。前人发现PRMT5在多种肿瘤细胞中表达量增高，但其与肿瘤发生之间的因果关系还甚为模糊。因此，这一研究结果将为人们深入了解蛋白质精氨酸甲基转移酶在肿瘤发生中的作用机制提供新的思路。
该研究结果在线发表于6月12日的PLoS Genetics杂志上，该实验室在读博士生杨玫、孙建伟为本论文的共同第一作者。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
