MTERF3 is a negative regulator of mammalian mtDNA transcription
MTERF3 is a negative regulator of mammalian mtDNA transcription
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DOI：
10.1016/j.cell.2007.05.046
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发表时间：
2007-07-27
期刊：
影响因子：
64.5
通讯作者：
Larsson, Nils-Goran
中科院分区：
文献类型：
--
作者：
Park, Chan Bae;Asin-Cayuela, Jorge;Larsson, Nils-Goran
哺乳动物mtDNA基因表达的调节对于改变氧化磷酸化能力以响应生理需求和疾病过程至关重要。启动mtDNA转录的基本机制已被分子定义，但对其活性的调节机制知之甚少。在这项研究中，我们表明，MTERF3是一个负调节线粒体DNA转录起始。MTERF3基因是必需的，因为纯合子敲除小鼠胚胎在妊娠中期死亡。心脏中MTERF3的组织特异性失活导致mtDNA转录异常和严重的呼吸链缺陷。MTERF3结合mtDNA启动子区域，并且MTERF3的缺失增加两条mtDNA链上的转录起始。这种增加的转录起始导致关键启动子远端tRNA基因的表达减少，这可能是通过环状mtDNA分子上的转录碰撞来解释的。据我们所知，MTERF3是第一个线粒体蛋白的例子，作为一个特定的阻遏物的哺乳动物mtDNA转录起始在体内。
Regulation of mammalian mtDNA gene expression is critical for altering oxidative phosphorylation capacity in response to physiological demands and disease processes. The basal machinery for initiation of mtDNA transcription has been molecularly defined, but the mechanisms regulating its activity are poorly understood. In this study, we show that MTERF3 is a negative regulator of mtDNA transcription initiation. The MTERF3 gene is essential because homozygous knockout mouse embryos die in midgestation. Tissue-specific inactivation of MTERF3 in the heart causes aberrant mtDNA transcription and severe respiratory chain deficiency. MTERF3 binds the mtDNA promoter region and depletion of MTERF3 increases transcription initiation on both mtDNA strands. This increased transcription initiation leads to decreased expression of critical promoter-distal tRNA genes, which is possibly explained by transcriptional collision on the circular mtDNA molecule. To our knowledge, MTERF3 is the first example of a mitochondrial protein that acts as a specific repressor of mammalian mtDNA transcription initiation in vivo.