Nuclear gene products that function in mitochondrial DNA replication.

Mammalian mitochondrial DNAs replicate unidirectionally from two distinct strand-specific origins. A round of replication begins at the heavy-strand origin (the D-loop) where transcripts from an upstream promoter serve as the primers for DNA synthesis. The transition from RNA to DNA synthesis occurs within short, conserved nucleotide sequence blocks and is mediated by specific endonucleolytic cleavage of the primary transcript. An enzymic component involved in the generation of primer RNA in mouse mitochondria has been identified. It is a sequence-specific endoribonuclease that cleaves single-stranded RNA substrate precisely at one of the transition sites. The other origin, that for light-strand synthesis, is located well apart on the genome and functions only when in a single-stranded template form. This origin has a defined secondary structure that is the most highly conserved sequence element in mammalian mitochondrial DNAs. Initiation of replication at this origin is by the action of a mitochondrial DNA primase, which is capable of synthesizing a short stretch of ribonucleotides before switching to DNA synthesis. Mitochondrial DNA primase appears to have an associated RNA species and the evidence to date suggests that components of both the D-loop endoribonuclease and the DNA primase are nuclear gene products.