Mitochondrial transcription factor A (mtTFA, mtTF1, TFAM) is an essential protein that binds mitochondrial DNA (mtDNA) with and without sequence specificity to regulate both mitochondrial transcription initiation and mtDNA copy number. The abundance of mtDNA generally reflects TFAM protein levels; however, the precise mechanism(s) by which this occurs remains a matter of debate. Data suggest that the usage of mitochondrial promoters is regulated by TFAM dosage, allowing TFAM to affect both gene expression and RNA priming for first strand mtDNA replication. Additionally, TFAM has a non-specific DNA binding activity that is both cooperative and high affinity. TFAM can compact plasmid DNA in vitro, suggesting a structural role for the non-specific DNA binding activity in genome packaging. This review summarizes TFAM-mtDNA interactions and describes an emerging view of TFAM as a multipurpose coordinator of mtDNA transactions, with direct consequences for the maintenance of gene expression and genome copy number. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.
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