The activity and specificity of ribonuclease H1, RNase H1, has been known for over half a century; like all enzymes in its class, it degrades RNA only when it is hybridized to DNA. However, the essential role of RNase H1 in mitochondrial DNA maintenance was not recognized until 2003, and empirical evidence that it is required to process RNA primers of mitochondrial DNA had to wait until 2015. In the same year, mutations in the RNASEH1 gene were linked to human mitochondrial diseases. The most recent studies suggest that in addition to primer-processing, RNase H1 determines the fate of R-loops, although not primarily those that might present an obstacle to DNA replication, but ones that contribute to the organization of mitochondrial DNA and the unusual mechanism of replication in mitochondria that utilizes transcripts for the strand-asynchronous mechanism of mitochondrial DNA replication. A full understanding of the role of RNase H1 in mtDNA metabolism will depend on further study, including careful consideration of its ability to stabilize, as well as to degrade RNA/DNA hybrids, and its regulation by oxidation or other mechanisms. Nevertheless, RNase H1 is already staking a strong claim to be the most versatile factor involved in propagating the DNA in the mitochondria.
Keywords: DNA replication; Mitochondrial DNA; Mitochondrial disease; Primers; R-loops; RNA/DNA hybrids; RNase H.
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