线粒体转录延伸因子:调控线粒体DNA复制与转录转换的分子开关

Mitochondrial Transcription Elongation Factors:A Replication-Transcription Switch in Human Mitochondria

线粒体转录延伸因子(TEFM)最早是基于其氨基酸序列与真核细胞核转录因子Spt6具有同源性而被鉴定,其包括两个串联重复的螺旋-发夹-螺旋结构域(Helix-Hairpin-Helix,(HhH)2)和一个RNase H折叠。TEFM二聚化对于TEFM与线粒体RNA聚合酶的结合至关重要。近年的研究发现,TEFM是调控线粒体DNA(mtDNA)复制与转录相互转换的关键分子开关,参与人类线粒体基因转录延伸过程及其表达调控。本文首先介绍了TEFM蛋白的序列同源性、蛋白质结构特征,为后续功能研究奠定结构基础。其次,阐明了TEFM在线粒体转录延伸过程中的作用和抗转录终止功能,以及线粒体转录延伸复合体的功能。TEFM避免了mtDNA转录和复制过程发生冲突,使线粒体转录延伸复合体具有更高的稳定性和持续合成能力,体内和体外都能增强mtDNA转录延伸活性,在mtDNA的复制和转录调控中发挥重要作用。最后,阐述了TEFM参与线粒体RNA加工,以及在线粒体能量代谢和线粒体相关疾病的发生发展中的作用。TEFM的缺失严重损害氧化呼吸链,证明mtDNA转录延伸对于维持线粒体氧化磷酸化功能是必需的。1型神经纤维瘤、胰腺癌、脑胶质瘤等疾病的发生机制可能与TEFM基因缺失或表达异常有关,因此,本文进一步探讨和展望了TEFM对人类线粒体相关疾病研究的应用前景。

The mitochondrial transcription elongation factor(TEFM)only exists in the metazoa.It was first identified based on its high sequence homology with the eukaryotic nuclear transcription factor Spt6,including two tandem repeats of the helix-hairpin-helical(HhH)domain and an RNase H-fold.The TEFM dimer structure is critical for the binding of TEFM to mtRNAP.In recent years,studies have found that TEFM is a key molecular switch that regulates mitochondrial genome replication and transcription,and participates in the human mitochondrial gene transcription extension process and its expression regulation.This paper first introduces the sequence homology and protein structural characteristics of the TEFM protein,and lays the structural foundation for subsequent functional research.Secondly,the role of TEFM in mitochondrial transcription elongation and the function of anti-transcription termination,as well as the function of the mitochondrial transcription elongation complex are clarified.TEFM avoids conflicts between mtDNA transcription and replication processes,and confers mitochondrial transcription extension complexes higher stability and continuous synthesis ability.It enhances mtDNA transcription extension activity in vivo and in vitro,and plays an important role in mtDNA replication and transcription regulation.Finally,the role of TEFM in mitochondrial RNA processing and the occurrence and development of mitochondrial energy metabolism and mitochondrial-related diseases are described.The deletion of TEFM severely impairs the function of oxidative phosphorylation of the respiratory chain,indicating that mtDNA transcriptional extension is necessary to maintain mitochondrial function.The pathogenesis of type 1 neurofibromas,pancreatic cancer,glioma and other diseases may be related to the deletion or abnormal expression of the TEFM gene.Therefore,this article further explores and prospects the application prospect of TEFM in human mitochondrial related diseases.