Mitochondrial transcription termination factor 1 directs polar replication fork pausing.
During replication of nuclear ribosomal DNA (rDNA), clashes with the transcription apparatus can cause replication fork collapse and genomic instability. To avoid this problem, a replication fork barrier protein is situated downstream of rDNA, there preventing replication in the direction opposite rDNA transcription. A potential candidate for a similar function in mitochondria is the mitochondrial transcription termination factor 1 (MTERF1, also denoted mTERF), which binds to a sequence just downstream of the ribosomal transcription unit. Previous studies have shown that MTERF1 prevents antisense transcription over the ribosomal RNA genes, a process which we here show to be independent of the transcription elongation factor TEFM. Importantly, we now demonstrate that MTERF1 arrests mitochondrial DNA (mtDNA) replication with distinct polarity. The effect is explained by the ability of MTERF1 to act as a directional contrahelicase, blocking mtDNA unwinding by the mitochondrial helicase TWINKLE. This conclusion is also supported by in vivo evidence that MTERF1 stimulates TWINKLE pausing. We conclude that MTERF1 can direct polar replication fork arrest in mammalian mitochondria.
Institute of Biomedicine, University of Gothenburg, P.O. Box 440, SE-405 30 Gothenburg, Sweden Center for Molecular Medicine, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
Yonghong
Y
Shi
Institute of Biomedicine, University of Gothenburg, P.O. Box 440, SE-405 30 Gothenburg, Sweden.
Viktor
V
Posse
Institute of Biomedicine, University of Gothenburg, P.O. Box 440, SE-405 30 Gothenburg, Sweden Center for Molecular Medicine, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
Xuefeng
X
Zhu
BioMediTech and Tampere University Hospital, FI-33014, University of Tampere, Finland.
Anne K
AK
Hyvärinen
BioMediTech and Tampere University Hospital, FI-33014, University of Tampere, Finland Institute of Biotechnology, FI-00014, University of Helsinki, Finland.
Howard T
HT
Jacobs
Institute of Biomedicine, University of Gothenburg, P.O. Box 440, SE-405 30 Gothenburg, Sweden claes.gustafsson@medkem.gu.se.
Maria
M
Falkenberg
Institute of Biomedicine, University of Gothenburg, P.O. Box 440, SE-405 30 Gothenburg, Sweden claes.gustafsson@medkem.gu.se.
Claes M
CM
Gustafsson
D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D004275:DNA, Ribosomal / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D012335:RNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D050976:Basic-Leucine Zipper Transcription Factors; D004272:DNA, Mitochondrial; D004275:DNA, Ribosomal; C105178:MTERF1 protein, human; D024101:Mitochondrial Proteins; D012335:RNA, Ribosomal; C560090:TEFM protein, human; D014157:Transcription Factors; D004265:DNA Helicases; C431576:TWNK protein, human