The accessory subunit B of DNA polymerase gamma is required for mitochondrial replisome function.
The mitochondrial replication machinery in human cells includes the DNA polymerase gamma holoenzyme and the TWINKLE helicase. Together, these two factors form a processive replication machinery, a replisome, which can use duplex DNA as template to synthesize long stretches of single-stranded DNA. We here address the importance of the smaller, accessory B subunit of DNA polymerase gamma and demonstrate that this subunit is absolutely required for replisome function. The duplex DNA binding activity of the B subunit is needed for coordination of POLgamma holoenzyme and TWINKLE helicase activities at the mtDNA replication fork. In the absence of proof for direct physical interactions between the components of the mitochondrial replisome, these functional interactions may explain the strict interdependence of TWINKLE and DNA polymerase gamma for mitochondrial DNA synthesis. Furthermore, mutations in TWINKLE as well as in the catalytic A and accessory B subunits of the POLgamma holoenzyme, may cause autosomal dominant progressive external ophthalmoplegia, a disorder associated with deletions in mitochondrial DNA. The crucial importance of the B subunit for replisome function may help to explain why mutations in these three proteins cause an identical syndrome.
Farge
Géraldine
G
Division of Metabolic Diseases, Karolinska Institutet, Novum, SE-141 86 Stockholm, Sweden.
Pham
Xuan Hoi
XH
Holmlund
Teresa
T
Khorostov
Ivan
I
Falkenberg
Maria
M
D004247:DNA / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D000074002:DNA Polymerase gamma; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000096:biosynthesis*; D004277:DNA, Single-Stranded / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes / Q000378:metabolism*; D009154:Mutation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013698:Templates, Genetic; D000099272:Replisomes
D004247:DNA; D004265:DNA Helicases; D000074002:DNA Polymerase gamma; D004272:DNA, Mitochondrial; D004277:DNA, Single-Stranded; D004259:DNA-Directed DNA Polymerase; D024101:Mitochondrial Proteins; D009097:Multienzyme Complexes; D021122:Protein Subunits; D000099272:Replisomes; C431576:TWNK protein, human