The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication

作者：Min Jiang, Xie Xie, Xuefeng Zhu, Shan Jiang, Dusanka Milenkovic, Jelena Misic, Yonghong Shi, Nirwan Tandukar, Xinping Li, Ilian Atanassov, Louise Jenninger, Emily Hoberg, Sara Albarran-Gutierrez, Zsolt Szilágyi, Bertil Macao, Stefan J. Siira, Valério Carelli, Jack D. Griffith, Claes M. Gustafsson, Thomas J. Nicholls, Aleksandra Filipovska, Nils‐Göran Larsson, Maria Falkenberg · 发表于：Science Advances · 年份：2021 · DOI：10.1126/sciadv.abf8631 · 被引用次数：71 · 研究领域：Mitochondrial Function and Pathology、Metabolism and Genetic Disorders、ATP Synthase and ATPases Research

We report a role for the mitochondrial single-stranded DNA binding protein (mtSSB) in regulating mitochondrial DNA (mtDNA) replication initiation in mammalian mitochondria. Transcription from the light-strand promoter (LSP) is required both for gene expression and for generating the RNA primers needed for initiation of mtDNA synthesis. In the absence of mtSSB, transcription from LSP is strongly up-regulated, but no replication primers are formed. Using deep sequencing in a mouse knockout model and biochemical reconstitution experiments with pure proteins, we find that mtSSB is necessary to restrict transcription initiation to optimize RNA primer formation at both origins of mtDNA replication. Last, we show that human pathological versions of mtSSB causing severe mitochondrial disease cannot efficiently support primer formation and initiation of mtDNA replication.