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3. Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion

Author

Misic, Jelena, primary, Milenkovic, Dusanka, additional, Al-Behadili, Ali, additional, Xie, Xie, additional, Jiang, Min, additional, Jiang, Shan, additional, Filograna, Roberta, additional, Koolmeister, Camilla, additional, Siira, Stefan J, additional, Jenninger, Louise, additional, Filipovska, Aleksandra, additional, Clausen, Anders R, additional, Caporali, Leonardo, additional, Valentino, Maria Lucia, additional, La Morgia, Chiara, additional, Carelli, Valerio, additional, Nicholls, Thomas J, additional, Wredenberg, Anna, additional, Falkenberg, Maria, additional, and Larsson, Nils-Göran, additional

Published
2022
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4. The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication

Author

Jiang, Min, primary, Xie, Xie, additional, Zhu, Xuefeng, additional, Jiang, Shan, additional, Milenkovic, Dusanka, additional, Misic, Jelena, additional, Shi, Yonghong, additional, Tandukar, Nirwan, additional, Li, Xinping, additional, Atanassov, Ilian, additional, Jenninger, Louise, additional, Hoberg, Emily, additional, Albarran-Gutierrez, Sara, additional, Szilagyi, Zsolt, additional, Macao, Bertil, additional, Siira, Stefan J., additional, Carelli, Valerio, additional, Griffith, Jack D., additional, Gustafsson, Claes M., additional, Nicholls, Thomas J., additional, Filipovska, Aleksandra, additional, Larsson, Nils-Göran, additional, and Falkenberg, Maria, additional

Published
2021
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5. A unique arginine cluster in PolDIP2 enhances nucleotide binding and DNA synthesis by PrimPol

Author

Kasho, Kazutoshi, Stojkovic, Gorazd, Velázquez-Ruiz, Cristina, Martínez-Jiménez, Maria Isabel, Doimo, Mara, Laurent, Timothée, Berner, Andreas, Pérez-Rivera, Aldo E., Jenninger, Louise, Blanco, Luis, Wanrooij, Sjoerd, Kasho, Kazutoshi, Stojkovic, Gorazd, Velázquez-Ruiz, Cristina, Martínez-Jiménez, Maria Isabel, Doimo, Mara, Laurent, Timothée, Berner, Andreas, Pérez-Rivera, Aldo E., Jenninger, Louise, Blanco, Luis, and Wanrooij, Sjoerd

Abstract

Replication forks often stall at damaged DNA. To overcome these obstructions and complete the DNA duplication in a timely fashion, replication can be restarted downstream of the DNA lesion. In mammalian cells, this repriming of replication can be achieved through the activities of primase and polymerase PrimPol. PrimPol is stimulated in DNA synthesis through interaction with PolDIP2, however the exact mechanism of this PolDIP2-dependent stimulation is still unclear. Here, we show that PrimPol uses a flexible loop to interact with the C-terminal ApaG-like domain of PolDIP2, and that this contact is essential for PrimPol's enhanced processivity. PolDIP2 increases primer-template and dNTP binding affinities of PrimPol, which concomitantly enhances its nucleotide incorporation efficiency. This stimulation is dependent on a unique arginine cluster in PolDIP2. Since the polymerase activity of PrimPol alone is very limited, this mechanism, where the affinity for dNTPs gets increased by PolDIP2 binding, might be critical for the in vivo function of PrimPol in tolerating DNA lesions at physiological nucleotide concentrations.

Published
2021
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6. A unique arginine cluster in PolDIP2 enhances nucleotide binding and DNA synthesis by PrimPol

Author

Kasho, Kazutoshi, primary, Stojkovič, Gorazd, additional, Velázquez-Ruiz, Cristina, additional, Martínez-Jiménez, Maria Isabel, additional, Doimo, Mara, additional, Laurent, Timothée, additional, Berner, Andreas, additional, Pérez-Rivera, Aldo E, additional, Jenninger, Louise, additional, Blanco, Luis, additional, and Wanrooij, Sjoerd, additional

Published
2021
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8. The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication.

Author

Min Jiang, Xie Xie, Xuefeng Zhu, Shan Jiang, Milenkovic, Dusanka, Misic, Jelena, Yonghong Shi, Tandukar, Nirwan, Xinping Li, Atanassov, Ilian, Jenninger, Louise, Hoberg, Emily, Albarran-Gutierrez, Sara, Szilagyi, Zsolt, Macao, Bertil, Siira, Stefan J., Carelli, Valerio, Griffith, Jack D., Gustafsson, Claes M., and Nicholls, Thomas J.

Subjects
*MITOCHONDRIAL DNA, *SINGLE-stranded DNA, *DNA-binding proteins, *GENE expression, *BIOCHEMICAL models
Abstract

We report a role for the mitochondrial single-stranded DNA binding protein (mtSSB) in regulating mitochondrial DNA (mtDNA) replication initiation in mammalian mitochondria. Transcription from the light-strand promoter (LSP) is required both for gene expression and for generating the RNA primers needed for initiation of mtDNA synthesis. In the absence of mtSSB, transcription from LSP is strongly up-regulated, but no replication primers are formed. Using deep sequencing in a mouse knockout model and biochemical reconstitution experiments with pure proteins, we find that mtSSB is necessary to restrict transcription initiation to optimize RNA primer formation at both origins of mtDNA replication. Last, we show that human pathological versions of mtSSB causing severe mitochondrial disease cannot efficiently support primer formation and initiation of mtDNA replication. [ABSTRACT FROM AUTHOR]

Published
2021
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9. Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion

Author

Jelena Misic, Dusanka Milenkovic, Ali Al-Behadili, Xie Xie, Min Jiang, Shan Jiang, Roberta Filograna, Camilla Koolmeister, Stefan J Siira, Louise Jenninger, Aleksandra Filipovska, Anders R Clausen, Leonardo Caporali, Maria Lucia Valentino, Chiara La Morgia, Valerio Carelli, Thomas J Nicholls, Anna Wredenberg, Maria Falkenberg, Nils-Göran Larsson, Misic, Jelena, Milenkovic, Dusanka, Al-Behadili, Ali, Xie, Xie, Jiang, Min, Jiang, Shan, Filograna, Roberta, Koolmeister, Camilla, Siira, Stefan J, Jenninger, Louise, Filipovska, Aleksandra, Clausen, Anders R, Caporali, Leonardo, Valentino, Maria Lucia, La Morgia, Chiara, Carelli, Valerio, Nicholls, Thomas J, Wredenberg, Anna, Falkenberg, Maria, and Larsson, Nils-Göran

Subjects
Mammals, DNA Replication, Mice, Animal, Ribonuclease H, Genetics, Animals, RNA, DNA, Mitochondrial, Mammal, Mitochondria
Abstract

The in vivo role for RNase H1 in mammalian mitochondria has been much debated. Loss of RNase H1 is embryonic lethal and to further study its role in mtDNA expression we characterized a conditional knockout of Rnaseh1 in mouse heart. We report that RNase H1 is essential for processing of RNA primers to allow site-specific initiation of mtDNA replication. Without RNase H1, the RNA:DNA hybrids at the replication origins are not processed and mtDNA replication is initiated at non-canonical sites and becomes impaired. Importantly, RNase H1 is also needed for replication completion and in its absence linear deleted mtDNA molecules extending between the two origins of mtDNA replication are formed accompanied by mtDNA depletion. The steady-state levels of mitochondrial transcripts follow the levels of mtDNA, and RNA processing is not altered in the absence of RNase H1. Finally, we report the first patient with a homozygous pathogenic mutation in the hybrid-binding domain of RNase H1 causing impaired mtDNA replication. In contrast to catalytically inactive variants of RNase H1, this mutant version has enhanced enzyme activity but shows impaired primer formation. This finding shows that the RNase H1 activity must be strictly controlled to allow proper regulation of mtDNA replication.

Published
2022
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