Failure to produce mitochondrial DNA results in embryonic lethality in Rnaseh1 null mice.
Although ribonucleases H (RNases H) have long been implicated in DNA metabolism, they are not required for viability in prokaryotes or unicellular eukaryotes. We generated Rnaseh1(-/-) mice to investigate the role of RNase H1 in mammals and observed developmental arrest at E8.5 in null embryos. A fraction of the mainly nuclear RNase H1 was targeted to mitochondria, and its absence in embryos resulted in a significant decrease in mitochondrial DNA content, leading to apoptotic cell death. This report links RNase H1 to generation of mitochondrial DNA, providing direct support for the strand-coupled mechanism of mitochondrial DNA replication. These findings also have important implications for therapy of mitochondrial dysfunctions and drug development for the structurally related RNase H of HIV.
Cerritelli
Susana M
SM
Laboratory of Molecular Genetics, National Institutes of Health, Bethesda, MD 20892, USA.
Frolova
Ella G
EG
Feng
Chiguang
C
Grinberg
Alexander
A
Love
Paul E
PE
Crouch
Robert J
RJ
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015139:Blotting, Southern; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000502:physiology*; D004579:Electron Transport; D005822:Genetic Vectors; D005838:Genotype; D006720:Homozygote; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D016914:Ribonuclease H / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors
D004272:DNA, Mitochondrial; D004247:DNA; D016914:Ribonuclease H