Mechanisms for quality control of RNA in mammalian cells

哺乳动物细胞 RNA 质量控制机制

• 批准号: 18370005
• 负责人: SEKIGUCHI Mutsuo
• 金额: $ 11万
• 依托单位: Fukuoka Dental College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18370005/
• 关键词: oxidative stress; RNA; oxidized guanine; ribonucleotide; mouse; quality control; genetic information; expression

The basal level of spontaneous errors in RNA synthesis is estimated to be 10^<-5> per residue, which is considerably higher than that for DNA replication, and the fidelity of transcription would be worse in an aerobic state. This means that numerous erroneous proteins are synthesized even in normal cells. Furthermore, the transcriptional fidelity would become lower when the RNA bases are modified by internal or external agents. Among such modifications, 8-oxoguanine (8-oxoG) is particularly important since this modified base causes base mispairing. It has been shown that the incorporation of 8-oxoG opposite the adenine residues of DNA by RNA polymerase causes a partial phenotypic suppression. In this case, although the majority of the proteins made are normal, some of the products are abnormal. Most of the erroneous proteins produced may be inactive, but some may exhibit dominant characteristics that can cause disorders of some cellular functions, which could thus lead to catastrophic consequences.8-oxoG can be formed in RNA by the incorporation of oxidized guanine nucleotide into RNA and also by the direct oxidation of the constituent guanine base in the RNA. In E coli, the MutT protein functions to prevent the former process while the PNP protein appears to be involved in the latter. Similar mechanisms seem to function in mammalian cells, but the situations are much more complex in comparison to the bacterial ones. At least two proteins with different substrate preferences, MTH1 and NUDT5, are involved in the former process, and also two different types of proteins, PNP and YB-1, are implicated with the latter process.

RNA合成中自发错误的基础水平估计为每个残基10^-5，这比DNA复制的水平高得多，并且转录的保真度在有氧状态下会更差。这意味着即使在正常细胞中也会合成许多错误的蛋白质。此外，当RNA碱基被内部或外部试剂修饰时，转录保真度会降低。在这些修饰中，8-氧代鸟嘌呤 (8-oxoG) 特别重要，因为这种修饰的碱基会导致碱基错配。已经表明，RNA聚合酶将8-oxoG掺入DNA的腺嘌呤残基对面会导致部分表型抑制。在这种情况下，虽然大部分产生的蛋白质是正常的，但有些产物是异常的。大多数产生的错误蛋白质可能是无活性的，但有些可能表现出显性特征，导致某些细胞功能紊乱，从而导致灾难性后果。通过将氧化鸟嘌呤核苷酸掺入RNA，可以在RNA中形成8-oxoG也可以通过 RNA 中鸟嘌呤碱基的直接氧化来实现。在大肠杆菌中，MutT 蛋白的作用是阻止前一过程，而 PNP 蛋白似乎参与了后者。类似的机制似乎在哺乳动物细胞中发挥作用，但与细菌细胞相比，情况要复杂得多。至少两种具有不同底物偏好的蛋白质 MTH1 和 NUDT5 参与前一过程，并且两种不同类型的蛋白质 PNP 和 YB-1 也参与后一过程。

项目成果

アルキル化損傷細胞にアポトーシスを誘導する新規遺伝子の同定

诱导烷基化损伤细胞凋亡的新基因的鉴定

• 发表时间: 2007
• 作者: 日高真純;他
• 通讯作者: 他

Modes of action of two types of anti-neoplastic drugs,dacarbnazine and ACNU,to induce apoptosis

达卡嗪和ACNU两类抗肿瘤药物诱导细胞凋亡的作用方式

• 发表时间: 2007
• 期刊: Carcinogenesis 28
• 作者: K.Shirasaki;T.Yamamura;Y.Monden;Y.Shiokawa;Masayuki Sanada
• 通讯作者: Masayuki Sanada

アルキル化発がんを抑制するアポトーシスの機構

细胞凋亡机制抑制烷基化致癌作用

• 发表时间: 2006
• 作者: Hiroshi Hayakawa;Ja-Eun Kim;Mutsuo Sekiguchi;Mutsuo Sekiguchi;Mutsuo Sekiguchi;Mutsuo Sekiguchi;Ja-Eun Kim;有森 貴夫;日高 真純;有森 貴夫;Masumi Hidaka;Mutsuo Sekiguchi;Nlasumi Hidaka;Mutsuo Sekiguchi;日高 真純;Masumi Hidaka;Mutsuo Sekiguchi;Masumi Hidaka;Mutsuo Sekiguchi;Nlaumi Hidaka;Mutsuo Sekiguchi;Hiroshi Hayakawa;Mutsuo Sekiguchi;Hiroshi Hayakawa;高木 康光;真田 正幸;高木 康光
• 通讯作者: 高木 康光

Modes of action of two types of anti-neoplastic drugs, dacarbnazine and ACNU, to induce aotosis

达卡嗪和 ACNU 两类抗肿瘤药物诱导耳鸣的作用方式

• 发表时间: 2007
• 期刊: Carcinogenesis 28
• 作者: K.Shirasaki;T.Yamamura;Y.Monden;Y.Shiokawa;Masayuki Sanada;Masayuki Sanada;Masayuki Sanada
• 通讯作者: Masayuki Sanada

Molecular devices for high fidelity of DNA replication and gene expression.

• DOI: 10.2183/pjab.82.278
• 发表时间: 2006-12
• 期刊: Proceedings of the Japan Academy. Series B, Physical and biological sciences
• 作者: Sekiguchi M