RBM5蛋白在mRNA选择性剪接中作用机制的研究
摘要
真核生物细胞中基因的表达受到mRNA剪接的调控,而mRNA选择性剪接保证了细胞中功能蛋白的多样性。在真核细胞中,mRNA剪接调控的精确性和有效性至关重要,而mRNA剪接缺陷往往和许多人类疾病相关。RBM5蛋白最初作为肿瘤抑制因子而被发现,RBM5蛋白过表达能够通过促进细胞凋亡和抑制细胞周期进程影响细胞的分裂增殖。近年来,有研究发现RBM5蛋白参与Fas、Caspase-2等细胞凋亡相关基因mRNA的选择性剪接调控,但是具体调控机制仍然不清楚。因此,本研究的主要目的在于探究RBM5参与mRNA选择性剪接调控的可能机制,为更好地理解RBM5的生物学功能提供线索。
1.RBM5蛋白对hAID mRNA选择性剪接的调控AID (Activation Induced Deaminase,活化诱导胞嘧啶核苷脱氨酶)是B细胞中类别转换(classs switch recombination)和体细胞高频突变(somatic hypermutation)两个过程所必需的,然而AID的不正常表达和B细胞淋巴瘤、肺癌、直肠癌等肿瘤的发生有密切关系。近年来,有研究发现AID mRNA选择性剪接是其生物学功能的重要调控环节。为了研究AID选择性剪接的调控机制,首先构建了含人AID第3、4、5外显子对应基因组DNA片段的真核表达载体。研究发现RBM5能够调控上述AID迷你基因的选择性剪接,促进外显子4的跳跃。我们进一步发现,RBM5蛋白的调控功能依赖于内含子3的3'剪接位点的强度。体外迁移率变动分析(gel mobility shift assay)实验结果表明,RBM5重组蛋白在体外能够结合AID mRNA,很可能是通过结合在内含子3的3’剪接位点上游发挥作用,提示RBM5蛋白可能通过结合在受调控外显子相关上游3’剪接位点附近,阻止剪接复合体对该3'剪接位点的识别,从而抑制相应内含子的剪切,促进外显子跳跃。
2.关于RBM5蛋白相互作用的研究mRNA剪接调控一般是通过RNA-RNA、RNA蛋白、蛋白-蛋白相互作用实现的。为了探寻与RBM5剪接调控相关的蛋白,本研究首先通过亲和纯化的方法从HeLa细胞核抽提物中分离了RBM5蛋白复合物,质谱分析鉴定出两个新的RBM5结合蛋白：DHX15和PRP19。免疫共沉淀和体外GST pulldown实验结果证实了RBM5蛋白能够结合DHX15和PRP19。已有研究表明,人DHX15的酵母同源蛋白Prp43p主要参与剪接体的解聚及核糖体rRNA的成熟,但DHX15在哺乳动物细胞中的作用目前尚不清楚。鉴于此,我们对RBM5与DHX15相互作用及其生物学意义进行更为深入的探索。首先,酵母双杂交和免疫共沉淀实验结果发现,RBM5 C端结构域是RBM5与DHX15间相互作用所必需的。进一步的点突变实验结果表明,RBM5 C端的Gpatch结构域对于RBM5与DHX15间的相互作用起到重要作用。最后,通过体外实验首次证实DHX15在体外具有解旋酶活性,而RBM5通过其G patch结构域促进DHX15的解旋酶活性。本研究为揭示RBM5蛋白调控mRNA选择性剪接的作用机制提供了新的线索。
In metazoan, most transcripts synthesized by RNA polymerase II carry non-coding intronic sequences that must be precisely removed by splicing to generate translatable messenger RNAs (mRNAs). Alternative splicing, a process to remove introns in different combinations, produces diverse mature mRNAs encoding distinct protein isoforms from a single gene. Therefore, accuracy, efficiency and regulation of splicing play critical roles in the modulation of gene expression in higher eukaryotes. RBM5 was originally characterized as candidate tumor suppressor gene in lung cancer. Elevated RBM5 expression inhibits cell proliferation by inducing apoptosis and cell cycle arrest in G1 phase. While RBM5 has the capacity to regulate alternative splicing of apoptosis-related genes, including Fas receptor, c-FLIP and caspase-2, underlying mechanisms remain largely elusive. In order to gain more insights in the biological function of RBM5 in alternative splicing, we performed following studies.
1. Regulation of hAID mRNA alternative splicing by RBM5
Activation Induced Deaminase (AID) was originally identified as a factor specifically expressed in active B cells. However, abnormal AID expression was also reported in several malignant tumors, such as B cell lymphomas, lung cancers and colorectal cancers. Interestingly, mRNA alternative splicing has recently been suggested to function in the regulation of AID expression. To investigate the mechanism of AID splicing regulation, we constructed a minigene in which a genomic DNA fragment containing exon 3/4/5 was inserted downstream to a CMV promoter. We found that RBM5 overexpression promotes AID exon 4 skipping in the minigene. Furthermore, our data showed that RBM5-mediated exon skipping requires a weak 3'splice site of intron 3. Gel mobility shift assays showed that recombinant RBM5 can bind immediately upstream of the 3'splice site of intron 3 in AID transcripts. The data present here suggest that RBM5 promotes human AID pre-mRNA exon 4 skipping and that this is most likely due to the interference of RBM5 on the recognition of 3'splice site by spliceosome.
2. Purification and identification of RBM5-associated protein complex
Splicing regulation is generally achieved through RNA-RNA, RNA-protein, or protein-protein interaction. To shed new light on the function of RBM5 in splicing regulation, affinity purification strategy was employed to purify RBM5-containing protein complexes from HeLa nuclear extract. DHX15 and PRP19, two versatile splicing factors, were identified as new RBM5-associated partners. Interaction between RBM5 and PRP19 were further confirmed by co-immunoprecipitation and in vitro GST pull-down assays. While yeast ortholog of DHX15 have been suggested to function in spliceosome disassembly and rRNA biogenesis, the biological function of DHX15 in mammalian cells remains largely unclear. We thus focused on characterization of the interaction between RBM5 and DHX15 in this study.
Yeast two-hybrid and co-immunoprecipitation assays showed that the carboxyl-terminal of RBM5 is required for the interaction with DHX15. Point mutation analysis indicated that G patch domain in the carboxyl terminus of RBM5 is indispensable for the interaction between RBM5 and DHX15. Finally, we provide the first evidence that recombinant DHX15 has an ATP-dependent helicase activity. Interestingly, recombinant RBM5 stimulates DHX15 helicase activity in vitro, suggesting of a potentially biological significance of the physical interaction between RBM5 and DHX15. Taken together, these findings provide new insights on the mechanisms by which RBM5 functions as a splicing regulator.
1.RBM5蛋白对hAID mRNA选择性剪接的调控AID (Activation Induced Deaminase,活化诱导胞嘧啶核苷脱氨酶)是B细胞中类别转换(classs switch recombination)和体细胞高频突变(somatic hypermutation)两个过程所必需的,然而AID的不正常表达和B细胞淋巴瘤、肺癌、直肠癌等肿瘤的发生有密切关系。近年来,有研究发现AID mRNA选择性剪接是其生物学功能的重要调控环节。为了研究AID选择性剪接的调控机制,首先构建了含人AID第3、4、5外显子对应基因组DNA片段的真核表达载体。研究发现RBM5能够调控上述AID迷你基因的选择性剪接,促进外显子4的跳跃。我们进一步发现,RBM5蛋白的调控功能依赖于内含子3的3'剪接位点的强度。体外迁移率变动分析(gel mobility shift assay)实验结果表明,RBM5重组蛋白在体外能够结合AID mRNA,很可能是通过结合在内含子3的3’剪接位点上游发挥作用,提示RBM5蛋白可能通过结合在受调控外显子相关上游3’剪接位点附近,阻止剪接复合体对该3'剪接位点的识别,从而抑制相应内含子的剪切,促进外显子跳跃。
2.关于RBM5蛋白相互作用的研究mRNA剪接调控一般是通过RNA-RNA、RNA蛋白、蛋白-蛋白相互作用实现的。为了探寻与RBM5剪接调控相关的蛋白,本研究首先通过亲和纯化的方法从HeLa细胞核抽提物中分离了RBM5蛋白复合物,质谱分析鉴定出两个新的RBM5结合蛋白：DHX15和PRP19。免疫共沉淀和体外GST pulldown实验结果证实了RBM5蛋白能够结合DHX15和PRP19。已有研究表明,人DHX15的酵母同源蛋白Prp43p主要参与剪接体的解聚及核糖体rRNA的成熟,但DHX15在哺乳动物细胞中的作用目前尚不清楚。鉴于此,我们对RBM5与DHX15相互作用及其生物学意义进行更为深入的探索。首先,酵母双杂交和免疫共沉淀实验结果发现,RBM5 C端结构域是RBM5与DHX15间相互作用所必需的。进一步的点突变实验结果表明,RBM5 C端的Gpatch结构域对于RBM5与DHX15间的相互作用起到重要作用。最后,通过体外实验首次证实DHX15在体外具有解旋酶活性,而RBM5通过其G patch结构域促进DHX15的解旋酶活性。本研究为揭示RBM5蛋白调控mRNA选择性剪接的作用机制提供了新的线索。
In metazoan, most transcripts synthesized by RNA polymerase II carry non-coding intronic sequences that must be precisely removed by splicing to generate translatable messenger RNAs (mRNAs). Alternative splicing, a process to remove introns in different combinations, produces diverse mature mRNAs encoding distinct protein isoforms from a single gene. Therefore, accuracy, efficiency and regulation of splicing play critical roles in the modulation of gene expression in higher eukaryotes. RBM5 was originally characterized as candidate tumor suppressor gene in lung cancer. Elevated RBM5 expression inhibits cell proliferation by inducing apoptosis and cell cycle arrest in G1 phase. While RBM5 has the capacity to regulate alternative splicing of apoptosis-related genes, including Fas receptor, c-FLIP and caspase-2, underlying mechanisms remain largely elusive. In order to gain more insights in the biological function of RBM5 in alternative splicing, we performed following studies.
1. Regulation of hAID mRNA alternative splicing by RBM5
Activation Induced Deaminase (AID) was originally identified as a factor specifically expressed in active B cells. However, abnormal AID expression was also reported in several malignant tumors, such as B cell lymphomas, lung cancers and colorectal cancers. Interestingly, mRNA alternative splicing has recently been suggested to function in the regulation of AID expression. To investigate the mechanism of AID splicing regulation, we constructed a minigene in which a genomic DNA fragment containing exon 3/4/5 was inserted downstream to a CMV promoter. We found that RBM5 overexpression promotes AID exon 4 skipping in the minigene. Furthermore, our data showed that RBM5-mediated exon skipping requires a weak 3'splice site of intron 3. Gel mobility shift assays showed that recombinant RBM5 can bind immediately upstream of the 3'splice site of intron 3 in AID transcripts. The data present here suggest that RBM5 promotes human AID pre-mRNA exon 4 skipping and that this is most likely due to the interference of RBM5 on the recognition of 3'splice site by spliceosome.
2. Purification and identification of RBM5-associated protein complex
Splicing regulation is generally achieved through RNA-RNA, RNA-protein, or protein-protein interaction. To shed new light on the function of RBM5 in splicing regulation, affinity purification strategy was employed to purify RBM5-containing protein complexes from HeLa nuclear extract. DHX15 and PRP19, two versatile splicing factors, were identified as new RBM5-associated partners. Interaction between RBM5 and PRP19 were further confirmed by co-immunoprecipitation and in vitro GST pull-down assays. While yeast ortholog of DHX15 have been suggested to function in spliceosome disassembly and rRNA biogenesis, the biological function of DHX15 in mammalian cells remains largely unclear. We thus focused on characterization of the interaction between RBM5 and DHX15 in this study.
Yeast two-hybrid and co-immunoprecipitation assays showed that the carboxyl-terminal of RBM5 is required for the interaction with DHX15. Point mutation analysis indicated that G patch domain in the carboxyl terminus of RBM5 is indispensable for the interaction between RBM5 and DHX15. Finally, we provide the first evidence that recombinant DHX15 has an ATP-dependent helicase activity. Interestingly, recombinant RBM5 stimulates DHX15 helicase activity in vitro, suggesting of a potentially biological significance of the physical interaction between RBM5 and DHX15. Taken together, these findings provide new insights on the mechanisms by which RBM5 functions as a splicing regulator.
引文
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