Abstract
RNase H1 is able to recognize DNA/RNA heteroduplexes and to degrade their RNA component. As a consequence, it has been implicated in different aspects of mtDNA replication such as primer formation, primer removal, and replication termination, and significant differences have been reported between control and mutant RNASEH1 skin fibroblasts from patients. However, neither mtDNA depletion nor the presence of deletions have been described in skin fibroblasts while still presenting signs of mitochondrial dysfunction (lower mitochondrial membrane potential, reduced oxygen consumption, slow growth in galactose). Here, we show that RNase H1 has an effect on mtDNA transcripts, most likely through the regulation of 7S RNA and other R-loops. The observed effect on both mitochondrial mRNAs and 16S rRNA results in decreased mitochondrial translation and subsequently mitochondrial dysfunction in cells carrying mutations in RNASEH1.
Highlights
Human mitochondrial DNA encodes 2 rRNAs, 22 tRNAs, and 13 out of 83 proteins that are subunits of the respiratory chain, while the remaining proteins required for mitochondrial function are encoded in the nucleus
We show that RNase H1 plays an important role in mitochondrial DNA (mtDNA) transcription
The nonsense mutation, c.469C > T (p.Arg157*), affects a residue at the N-terminus of the catalytic domain and, as a consequence, the truncated protein is void of any activity (Reyes et al, 2015)
Summary
Human mitochondrial DNA (mtDNA) encodes 2 rRNAs, 22 tRNAs, and 13 out of 83 proteins that are subunits of the respiratory chain, while the remaining proteins required for mitochondrial function are encoded in the nucleus. All proteins responsible for mtDNA maintenance, especially those involved in replication, as well as other proteins necessary for transcription and translation, are encoded in the nucleus (Gustafsson et al, 2016). Human mtDNA replication requires several factors that constitute the replisome and that include DNA polymerase subunits POLG and POLG2, the helicase TWNK, the single-stranded binding protein SSBP1, and DNA topoisomerases TOP1, TOP2A and TOP2B (Gustafsson et al, 2016). The hybrid binding domain is responsible for the recognition of the DNA/RNA hybrids, and it enhances both the specific activity and the processivity of the enzyme (Nowotny et al, 2008).
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