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  • 1.
    Calvo, Patricia A
    et al.
    Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
    Martínez-Jiménez, María I
    Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
    Díaz, Marcos
    Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
    Stojkovic, Gorazd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kasho, Kazutoshi
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain; Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
    Guerra, Susana
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Méndez, Juan
    Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
    Blanco, Luis
    Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
    Motif WFYY of human PrimPol is crucial to stabilize the incoming 3'-nucleotide during replication fork restart2021In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 49, no 14, p. 8199-8213Article in journal (Refereed)
    Abstract [en]

    PrimPol is the second primase in human cells, the first with the ability to start DNA chains with dNTPs. PrimPol contributes to DNA damage tolerance by restarting DNA synthesis beyond stalling lesions, acting as a TLS primase. Multiple alignment of eukaryotic PrimPols allowed us to identify a highly conserved motif, WxxY near the invariant motif A, which contains two active site metal ligands in all members of the archeo-eukaryotic primase (AEP) superfamily. In vivo and in vitro analysis of single variants of the WFYY motif of human PrimPol demonstrated that the invariant Trp87 and Tyr90 residues are essential for both primase and polymerase activities, mainly due to their crucial role in binding incoming nucleotides. Accordingly, the human variant F88L, altering the WFYY motif, displayed reduced binding of incoming nucleotides, affecting its primase/polymerase activities especially during TLS reactions on UV-damaged DNA. Conversely, the Y89D mutation initially associated with High Myopia did not affect the ability to rescue stalled replication forks in human cells. Collectively, our data suggest that the WFYY motif has a fundamental role in stabilizing the incoming 3'-nucleotide, an essential requisite for both its primase and TLS abilities during replication fork restart.

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  • 2.
    Inatomi, Teppei
    et al.
    Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka-shi, Japan.
    Matsuda, Shigeru
    Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka-shi, Japan; Department of Modomics Biology and Medicine, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryocho, Aoba-ku, Miyagi, Sendai-shi, Japan.
    Ishiuchi, Takashi
    Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka-shi, Japan.
    Do, Yura
    Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka-shi, Japan.
    Nakayama, Masunari
    Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka-shi, Japan.
    Abe, Shusaku
    Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka-shi, Japan.
    Kasho, Kazutoshi
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Nakada, Kazuto
    Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennoudai, Ibaraki, Tsukuba-shi, Japan.
    Ichiyanagi, Kenji
    Department of Animal Sciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Aichi, Nagoya-shi, Japan.
    Sasaki, Hiroyuki
    Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka-shi, Japan.
    Yasukawa, Takehiro
    Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka-shi, Japan; Department of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, Japan.
    Kang, Dongchon
    Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka-shi, Japan.
    TFB2M and POLRMT are essential for mammalian mitochondrial DNA replication2022In: Biochimica et Biophysica Acta. Molecular Cell Research, ISSN 0167-4889, E-ISSN 1879-2596, Vol. 1869, no 1, article id 119167Article in journal (Refereed)
    Abstract [en]

    Two classes of replication intermediates have been observed from mitochondrial DNA (mtDNA) in many mammalian tissue and cells with two-dimensional agarose gel electrophoresis. One is assigned to leading-strand synthesis in the absence of synchronous lagging-strand synthesis (strand-asynchronous replication), and the other has properties of coupled leading- and lagging-strand synthesis (strand-coupled replication). While strand-asynchronous replication is primed by long noncoding RNA synthesized from a defined transcription initiation site, little is known about the commencement of strand-coupled replication. To investigate it, we attempted to abolish strand-asynchronous replication in cultured human cybrid cells by knocking out the components of the transcription initiation complexes, mitochondrial transcription factor B2 (TFB2M/mtTFB2) and mitochondrial RNA polymerase (POLRMT/mtRNAP). Unexpectedly, removal of either protein resulted in complete mtDNA loss, demonstrating for the first time that TFB2M and POLRMT are indispensable for the maintenance of human mtDNA. Moreover, a lack of TFB2M could not be compensated for by mitochondrial transcription factor B1 (TFB1M/mtTFB1). These findings indicate that TFB2M and POLRMT are crucial for the priming of not only strand-asynchronous but also strand-coupled replication, providing deeper insights into the molecular basis of mtDNA replication initiation.

  • 3.
    Jamroskovic, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Doimo, Mara
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chand, Karam
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Obi, Ikenna
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kumar, Rajendra
    Umeå University, Faculty of Science and Technology, Department of Physics. Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Hedenström, Mattias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Das, Rabindra Nath
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Akhunzianov, Almaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia.
    Deiana, Marco
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Kasho, Kazutoshi
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Sulis Sato, Sebastian
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pourbozorgi-Langroudi, Parham
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mason, James E.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Medini, Paolo
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Öhlund, Daniel
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Chorell, Erik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Sabouri, Nasim
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization2020In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 142, no 6, p. 2876-2888Article in journal (Refereed)
    Abstract [en]

    The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.

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  • 4.
    Kasho, Kazutoshi
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Krasauskas, Lukas
    Life Sciences Center, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.
    Smirnovas, Vytautas
    Life Sciences Center, Institute of Biotechnology, Vilnius University, Vilnius, Lithuania.
    Stojkovic, Gorazd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Human polymerase δ-interacting protein 2 (Poldip2) inhibits the formation of human tau oligomers and fibrils2021In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 22, no 11, article id 5768Article in journal (Refereed)
    Abstract [en]

    A central characteristic of Alzheimer’s disease (AD) and other tauopathies is the accumulation of aggregated and misfolded Tau deposits in the brain. Tau-targeting therapies for AD have been unsuccessful in patients to date. Here we show that human polymerase δ-interacting protein 2 (PolDIP2) interacts with Tau. With a set of complementary methods, including thioflavin-T-based aggregation kinetic assays, Tau oligomer-specific dot-blot analysis, and single oligomer/fibril analysis by atomic force microscopy, we demonstrate that PolDIP2 inhibits Tau aggregation and amyloid fibril growth in vitro. The identification of PolDIP2 as a potential regulator of cellular Tau aggregation should be considered for future Tau-targeting therapeutics.

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  • 5.
    Kasho, Kazutoshi
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Stojkovic, Gorazd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Velázquez-Ruiz, Cristina
    Centro de Biologia Molecular Severo Ochoa, Madrid, Spain.
    Martínez-Jiménez, Maria Isabel
    Centro de Biologia Molecular Severo Ochoa, Madrid, Spain.
    Doimo, Mara
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Laurent, Timothée
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Berner, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Pérez-Rivera, Aldo E.
    Centro de Biologia Molecular Severo Ochoa, Madrid, Spain.
    Jenninger, Louise
    Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
    Blanco, Luis
    Centro de Biologia Molecular Severo Ochoa, Madrid, Spain.
    Wanrooij, Sjoerd
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    A unique arginine cluster in PolDIP2 enhances nucleotide binding and DNA synthesis by PrimPol2021In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 49, no 4, p. 2179-2191Article in journal (Refereed)
    Abstract [en]

    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.

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  • 6. Taniguchi, Saki
    et al.
    Kasho, Kazutoshi
    Department of Molecular Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
    Ozaki, Shogo
    Katayama, Tsutomu
    Escherichia coli CrfC Protein, a Nucleoid Partition Factor, Localizes to Nucleoid Poles via the Activities of Specific Nucleoid-Associated Proteins2019In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 10, article id 72Article in journal (Refereed)
    Abstract [en]

    The Escherichia coli CrfC protein is an important regulator of nucleoid positioning and equipartition. Previously we revealed that CrfC homo-oligomers bind the clamp, a DNA-binding subunit of the DNA polymerase III holoenzyme, promoting colocalization of the sister replication forks, which ensures the nucleoid equipartition. In addition, CrfC localizes at the cell pole-proximal loci via an unknown mechanism. Here, we demonstrate that CrfC localizes to the distinct subnucleoid structures termed nucleoid poles (the cell pole-proximal nucleoid-edges) even in elongated cells as well as in wild-type cells. Systematic analysis of the nucleoid-associated proteins (NAPs) and related proteins revealed that HU, the most abundant NAP, and SImA, the nucleoid occlusion factor regulating the localization of cell division apparatus, promote the specific localization of CrfC foci. When the replication initiator DnaA was inactivated, SImA and HU were required for formation of CrfC foci. In contrast, when the replication initiation was inhibited with a specific mutant of the helicase-loader DnaC, CrfC foci were sustained independently of SImA and HU. H-NS, which forms clusters on AT-rich DNA regions, promotes formation of CrfC foci as well as transcriptional regulation of crfC. In addition, MukB, the chromosomal structure mainetanice protein, and SeqA, a hemimethylated nascent DNA region-binding protein, moderately stimulated formation of CrfC foci. However, IHF, a structural homolog of HU, MatP, the replication terminus-binding protein, Dps, a stress-response factor, and FtsZ, an SImA-interacting factor in cell division apparatus, little or only slightly affected CrfC foci formation and localization. Taken together, these findings suggest a novel and unique mechanism that CrfC localizes to the nucleoid poles in two steps, assembly and recruitment, dependent upon HU, MukB, SeqA, and SImA, which is stimulated directly or indirectly by H-NS and DnaA. These factors might concordantly affect specific nucleoid substructures. Also, these nucleoid dynamics might be significant in the role for CrfC in chromosome partition.

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