microRNA (miRNA) 生物发生
中文名称
通路描述
microRNA (miRNA) 生物发生 miRNA 的生物发生可概括为五个步骤 (综述见 Ketting 2011, Nowotny and Yang 2009, Kim et al. 2009, Chua et al. 2009, Hannon and He 2004):
1. 转录。miRNA 转录本可能来自自主转录基因，它们可能与其他基因共转录，或位于宿主基因的内含子中。大多数 miRNA 由 RNA 聚合酶 II 转录，但少数 miRNA 作为 RNA 聚合酶 III 共转录本与相邻重复元件产生。初始转录本称为初级 miRNA (pri-miRNA)，包含一个不完整的双链区域位于发夹环内。更长的序列从发夹环的 5' 和 3' 端延伸，并可能也包含双链区域。
2. DROSHA 切割。pri-miRNA 的 5' 和 3' 端在 DROSHA 核酸酶与 RNA 结合蛋白 DGCR8 的复合物中通过内切核酸酶切割被移除。切割产物称为约 60 到 70 nt 的短发夹，称为前 miRNA (pre-miRNA)。
3. 核输出由 Exportin-5。前 miRNA 与 Ran 和 GTP 结合后与 Exportin-5 结合。复合物将前 miRNA 通过核孔转运至细胞质。
4. DICER1 切割。一旦进入细胞质，前 miRNA 与 RISC 加载复合物结合，该复合物包含 DICER1、一种 Argonaute 蛋白以及 TARBP2 或 PRKRA。DICER1 切割前 miRNA 产生约 21 到 23 个核苷酸的不完整双链 miRNA。在此阶段，双链 miRNA 具有突出的 3' 单链末端，长度为 2-3 nt。
5. 整合入 RNA 诱导沉默复合体 (RISC) 和链选择。双链 miRNA 被整合到 RISC 加载复合物中的 Argonaute 蛋白。一条链，乘客链，将被移除并降解；另一条链，引导链，将被保留，并引导 Argonaute:miRNA 复合体 (RISC) 靶向 mRNA。
人类基因组编码 4 种 Argonaute 蛋白 (AGO1 (EIF2C1), AGO2 (EIF2C2), AGO3 (EIF2C3), AGO4 (EIF2C4))，但只有 AGO2 (EIF2C2) 能够与引导 miRNA 具有完美或近乎完美的互补性来切割靶 mRNA。对于包含 AGO2 的复合物，双链 miRNA 乘客链的切割伴随着乘客链的移除。包含其他 Argonautes 的复合物可能使用解旋酶移除乘客链，但尚不完全清楚。最终装载到 AGO2 的 miRNA 主要位于 TARBP2 或 PRKRA 复合物中，位于粗面内质网胞质面。AGO2、TARBP2 和 DICER1 也在细胞核中观察到。
1. 转录。miRNA 转录本可能来自自主转录基因，它们可能与其他基因共转录，或位于宿主基因的内含子中。大多数 miRNA 由 RNA 聚合酶 II 转录，但少数 miRNA 作为 RNA 聚合酶 III 共转录本与相邻重复元件产生。初始转录本称为初级 miRNA (pri-miRNA)，包含一个不完整的双链区域位于发夹环内。更长的序列从发夹环的 5' 和 3' 端延伸，并可能也包含双链区域。
2. DROSHA 切割。pri-miRNA 的 5' 和 3' 端在 DROSHA 核酸酶与 RNA 结合蛋白 DGCR8 的复合物中通过内切核酸酶切割被移除。切割产物称为约 60 到 70 nt 的短发夹，称为前 miRNA (pre-miRNA)。
3. 核输出由 Exportin-5。前 miRNA 与 Ran 和 GTP 结合后与 Exportin-5 结合。复合物将前 miRNA 通过核孔转运至细胞质。
4. DICER1 切割。一旦进入细胞质，前 miRNA 与 RISC 加载复合物结合，该复合物包含 DICER1、一种 Argonaute 蛋白以及 TARBP2 或 PRKRA。DICER1 切割前 miRNA 产生约 21 到 23 个核苷酸的不完整双链 miRNA。在此阶段，双链 miRNA 具有突出的 3' 单链末端，长度为 2-3 nt。
5. 整合入 RNA 诱导沉默复合体 (RISC) 和链选择。双链 miRNA 被整合到 RISC 加载复合物中的 Argonaute 蛋白。一条链，乘客链，将被移除并降解；另一条链，引导链，将被保留，并引导 Argonaute:miRNA 复合体 (RISC) 靶向 mRNA。
人类基因组编码 4 种 Argonaute 蛋白 (AGO1 (EIF2C1), AGO2 (EIF2C2), AGO3 (EIF2C3), AGO4 (EIF2C4))，但只有 AGO2 (EIF2C2) 能够与引导 miRNA 具有完美或近乎完美的互补性来切割靶 mRNA。对于包含 AGO2 的复合物，双链 miRNA 乘客链的切割伴随着乘客链的移除。包含其他 Argonautes 的复合物可能使用解旋酶移除乘客链，但尚不完全清楚。最终装载到 AGO2 的 miRNA 主要位于 TARBP2 或 PRKRA 复合物中，位于粗面内质网胞质面。AGO2、TARBP2 和 DICER1 也在细胞核中观察到。
英文描述
MicroRNA (miRNA) biogenesis Biogenesis of microRNAs (miRNAs) can be summarized in five steps (reviewed in Ketting 2011, Nowotny and Yang 2009, Kim et al. 2009, Chua et al. 2009, Hannon and He 2004):
1. Transcription. miRNA transcripts may come from autonomously transcribed genes, they may be contained in cotranscripts with other genes, or they may be located in introns of host genes. Most miRNAs are transcribed by RNA polymerase II, however a few miRNAs originate as RNA polymerase III cotranscripts with neighboring repetitive elements. The initial transcript, termed a primary microRNA (pri-miRNA), contains an imperfectly double-stranded region within a hairpin loop. Longer sequences extend from the 5' and 3' ends of the hairpin and may also contain double-stranded regions.
2. Cleavage by DROSHA. The 5' and 3' ends of the pri-miRNA are removed during endoribonucleolytic cleavage by the DROSHA nuclease in a complex with the RNA-binding protein DGCR8 (the Microprocessor complex). The cleavage product is a short hairpin of about 60 to 70 nt called the pre-microRNA (pre-miRNA).
3. Nuclear export by Exportin-5. The resulting pre-miRNA is bound by Exportin-5 in a complex with Ran and GTP. The complex translocates the pre-miRNA through the nuclear pore into the cytoplasm.
4. Cleavage by DICER1. Once in the cytoplasm the pre-miRNA is bound by the RISC loading complex which contains DICER1, an Argonaute protein and either TARBP2 or PRKRA. DICER1 cleaves the pre-miRNA to yield an imperfectly double-stranded miRNA of about 21 to 23 nucleotides. At this stage the double-stranded miRNA has protruding single-stranded 3' ends of 2-3 nt.
5. Incorporation into RNA-Induced Silencing Complex (RISC) and strand selection. The double-stranded miRNA is passed to a Argonaute protein contained in the RISC loading complex. One strand, the passenger strand, will be removed and degraded; the other strand, the guide strand, will be retained and will guide the Argonaute:miRNA complex (RISC) to target mRNAs.
The human genome encodes 4 Argonaute proteins (AGO1 (EIF2C1), AGO2 (EIF2C2), AGO3 (EIF2C3), AGO4 (EIF2C4)), however only AGO2 (EIF2C2) can cleave target mRNAs with perfect or nearly perfect complementarity to the guide miRNA. For complexes that contain AGO2, cleavage of the passenger strand of the double-stranded miRNA accompanies removal of the passenger strand. Complexes containing other Argonautes may use a helicase to remove the passenger strand but this is not fully known. The resulting miRNA-loaded AGO2 is predominantly located in complexes with TARBP2 or PRKRA at the cytosolic face of the rough endoplasmic reticulum. AGO2, TARBP2, and DICER1 are also observed in the nucleus.
1. Transcription. miRNA transcripts may come from autonomously transcribed genes, they may be contained in cotranscripts with other genes, or they may be located in introns of host genes. Most miRNAs are transcribed by RNA polymerase II, however a few miRNAs originate as RNA polymerase III cotranscripts with neighboring repetitive elements. The initial transcript, termed a primary microRNA (pri-miRNA), contains an imperfectly double-stranded region within a hairpin loop. Longer sequences extend from the 5' and 3' ends of the hairpin and may also contain double-stranded regions.
2. Cleavage by DROSHA. The 5' and 3' ends of the pri-miRNA are removed during endoribonucleolytic cleavage by the DROSHA nuclease in a complex with the RNA-binding protein DGCR8 (the Microprocessor complex). The cleavage product is a short hairpin of about 60 to 70 nt called the pre-microRNA (pre-miRNA).
3. Nuclear export by Exportin-5. The resulting pre-miRNA is bound by Exportin-5 in a complex with Ran and GTP. The complex translocates the pre-miRNA through the nuclear pore into the cytoplasm.
4. Cleavage by DICER1. Once in the cytoplasm the pre-miRNA is bound by the RISC loading complex which contains DICER1, an Argonaute protein and either TARBP2 or PRKRA. DICER1 cleaves the pre-miRNA to yield an imperfectly double-stranded miRNA of about 21 to 23 nucleotides. At this stage the double-stranded miRNA has protruding single-stranded 3' ends of 2-3 nt.
5. Incorporation into RNA-Induced Silencing Complex (RISC) and strand selection. The double-stranded miRNA is passed to a Argonaute protein contained in the RISC loading complex. One strand, the passenger strand, will be removed and degraded; the other strand, the guide strand, will be retained and will guide the Argonaute:miRNA complex (RISC) to target mRNAs.
The human genome encodes 4 Argonaute proteins (AGO1 (EIF2C1), AGO2 (EIF2C2), AGO3 (EIF2C3), AGO4 (EIF2C4)), however only AGO2 (EIF2C2) can cleave target mRNAs with perfect or nearly perfect complementarity to the guide miRNA. For complexes that contain AGO2, cleavage of the passenger strand of the double-stranded miRNA accompanies removal of the passenger strand. Complexes containing other Argonautes may use a helicase to remove the passenger strand but this is not fully known. The resulting miRNA-loaded AGO2 is predominantly located in complexes with TARBP2 or PRKRA at the cytosolic face of the rough endoplasmic reticulum. AGO2, TARBP2, and DICER1 are also observed in the nucleus.
所含基因
24 个基因