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  • 1. Al-Behadili, Ali
    et al.
    Uhler, Jay P.
    Berglund, Anna-Karin
    Peter, Bradley
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Reyes, Aurelio
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Zeviani, Massimo
    Falkenberg, Maria
    A two-nuclease pathway involving RNase H1 is required for primer removal at human mitochondrial OriL2018Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, nr 18, s. 9471-9483Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The role of Ribonuclease H1 (RNase H1) during primer removal and ligation at the mitochondrial origin of light-strand DNA synthesis (OriL) is a key, yet poorly understood, step in mitochondrial DNA maintenance. Here, we reconstitute the replication cycle of L-strand synthesis in vitro using recombinant mitochondrial proteins and model OriL substrates. The process begins with initiation of DNA replication at OriL and ends with primer removal and ligation. We find that RNase H1 partially removes the primer, leaving behind the last one to three ribonucleotides. These 5′-end ribonucleotides disturb ligation, a conclusion which is supported by analysis of RNase H1-deficient patient cells. A second nuclease is therefore required to remove the last ribonucleotides and we demonstrate that Flap endonuclease 1 (FEN1) can execute this function in vitro. Removal of RNA primers at OriL thus depends on a two-nuclease model, which in addition to RNase H1 requires FEN1 or a FEN1-like activity. These findings define the role of RNase H1 at OriL and help to explain the pathogenic consequences of disease causing mutations in RNase H1.

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  • 2.
    Andréasson, Måns
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Donzel, Maxime
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Berner, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Clinical Genetics Unit, Department of Women and Children’s Health, Padua University, Padua, Italy.
    Quiroga, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Eriksson, Anna U.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chao, Yu-Kai
    Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, United Kingdom.
    Overman, Jeroen
    Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, United Kingdom.
    Pemberton, Nils
    Medicinal Chemistry, Research and Early Development, Respiratory and Immunology (R&I), Bio Pharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Exploring the dispersion and electrostatic components in arene-arene interactions between ligands and G4 DNA to develop G4-ligands2024Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 67, nr 3, s. 2202-2219Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    G-Quadruplex (G4) DNA structures are important regulatory elements in central biological processes. Small molecules that selectively bind and stabilize G4 structures have therapeutic potential, and there are currently >1000 known G4 ligands. Despite this, only two G4 ligands ever made it to clinical trials. In this work, we synthesized several heterocyclic G4 ligands and studied their interactions with G4s (e.g., G4s from the c-MYC, c-KIT, and BCL-2 promoters) using biochemical assays. We further studied the effect of selected compounds on cell viability, the effect on the number of G4s in cells, and their pharmacokinetic properties. This identified potent G4 ligands with suitable properties and further revealed that the dispersion component in arene-arene interactions in combination with electron-deficient electrostatics is central for the ligand to bind with the G4 efficiently. The presented design strategy can be applied in the further development of G4-ligands with suitable properties to explore G4s as therapeutic targets.

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  • 3.
    Andréasson, Måns
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Donzel, Maxime
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Berner, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Quiroga, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pemberton, Nils
    AstraZeneca, Gothenburg, Sweden.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    The Synergism of the Dispersion and Electrostatic Components in the Arene-Arene Interactions Between Ligands and G4 DNAManuskript (preprint) (Övrigt vetenskapligt)
  • 4.
    Berner, Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Das, Rabindra Nath
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bhuma, Naresh
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Golebiewska, Justyna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andréasson, Måns
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chaudhari, Namrata
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Bose, Partha Pratim
    Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Huddinge, Sweden.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Strömberg, Roger
    Department of Biosciences and Nutrition, Karolinska Institutet, Neo, Huddinge, Sweden.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    G4-ligand-conjugated oligonucleotides mediate selective binding and stabilization of individual G4 DNA structures2023Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 146, nr 10, s. 6926-6935Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    G-quadruplex (G4) DNA structures are prevalent secondary DNA structures implicated in fundamental cellular functions, such as replication and transcription. Furthermore, G4 structures are directly correlated to human diseases such as cancer and have been highlighted as promising therapeutic targets for their ability to regulate disease-causing genes, e.g., oncogenes. Small molecules that bind and stabilize these structures are thus valuable from a therapeutic perspective and helpful in studying the biological functions of the G4 structures. However, there are hundreds of thousands of G4 DNA motifs in the human genome, and a long-standing problem in the field is how to achieve specificity among these different G4 structures. Here, we developed a strategy to selectively target an individual G4 DNA structure. The strategy is based on a ligand that binds and stabilizes G4s without selectivity, conjugated to a guide oligonucleotide, that specifically directs the G4-Ligand-conjugated oligo (GL-O) to the single target G4 structure. By employing various biophysical and biochemical techniques, we show that the developed method enables the targeting of a unique, specific G4 structure without impacting other off-target G4 formations. Considering the vast amount of G4s in the human genome, this represents a promising strategy to study the presence and functions of individual G4s but may also hold potential as a future therapeutic modality.

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  • 5. Cerqua, Cristina
    et al.
    Morbidoni, Valeria
    Desbats, Maria Andrea
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Clinical Genetics Unit, Department of Women and Children's Health, University of Padova, Padova, Italy.
    Frasson, Chiara
    Sacconi, Sabrina
    Baldoin, Maria Cristina
    Sartori, Geppo
    Basso, Giuseppe
    Salviati, Leonardo
    Trevisson, Eva
    COX16 is required for assembly of cytochrome c oxidase in human cells and is involved in copper delivery to COX22018Ingår i: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1859, nr 4, s. 244-252Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cytochrome c oxidase (COX), complex IV of the mitochondrial respiratory chain, is comprised of 14 structural subunits, several prosthetic groups and metal cofactors, among which copper. Its biosynthesis involves a number of ancillary proteins, encoded by the COX-assembly genes that are required for the stabilization and membrane insertion of the nascent polypeptides, the synthesis of the prosthetic groups, and the delivery of the metal cofactors, in particular of copper. Recently, a modular model for COX assembly has been proposed, based on the sequential incorporation of different assembly modules formed by specific subunits.

    We have cloned and characterized the human homologue of yeast COX16. We show that human COX16 encodes a small mitochondrial transmembrane protein that faces the intermembrane space and is highly expressed in skeletal and cardiac muscle. Its knockdown in C. elegans produces COX deficiency, and its ablation in HEK293 cells impairs COX assembly. Interestingly, COX16 knockout cells retain significant COX activity, suggesting that the function of COX16 is partially redundant.

    Analysis of steady-state levels of COX subunits and of assembly intermediates by Blue-Native gels shows a pattern similar to that reported in cells lacking COX18, suggesting that COX16 is required for the formation of the COX2 subassembly module. Moreover, COX16 co-immunoprecipitates with COX2. Finally, we found that copper supplementation increases COX activity and restores normal steady state levels of COX subunits in COX16 knockout cells, indicating that, even in the absence of a canonical copper binding motif, COX16 could be involved in copper delivery to COX2.

  • 6.
    Das, Rabindra Nath
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Berner, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Bhuma, Naresh
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Golebiewska, Justyna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andréasson, Måns
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Chaudhari, Namrata
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Development of a G4 Ligand-Conjugated Oligonucleotide Modality that Selectively Targets Individual G4 DNA StructuresManuskript (preprint) (Övrigt vetenskapligt)
  • 7.
    Doimo, Mara
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Department of Women and Children Health, University of Padova, Padova, Italy.
    Chaudhari, Namrata
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Abrahamsson, Sanna
    Bioinformatics and Data Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    L'Hôte, Valentin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Nguyen, Tran V. H.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Berner, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Ndi, Mama
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Abrahamsson, Alva
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Das, Rabindra Nath
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Aasumets, Koit
    Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland.
    Goffart, Steffi
    Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland.
    Pohjoismäki, Jaakko L. O.
    Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland.
    López, Marcela Dávila
    Bioinformatics and Data Centre, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Enhanced mitochondrial G-quadruplex formation impedes replication fork progression leading to mtDNA loss in human cells2023Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 51, nr 14, s. 7392-7408Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mitochondrial DNA (mtDNA) replication stalling is considered an initial step in the formation of mtDNA deletions that associate with genetic inherited disorders and aging. However, the molecular details of how stalled replication forks lead to mtDNA deletions accumulation are still unclear. Mitochondrial DNA deletion breakpoints preferentially occur at sequence motifs predicted to form G-quadruplexes (G4s), four-stranded nucleic acid structures that can fold in guanine-rich regions. Whether mtDNA G4s form in vivo and their potential implication for mtDNA instability is still under debate. In here, we developed new tools to map G4s in the mtDNA of living cells. We engineered a G4-binding protein targeted to the mitochondrial matrix of a human cell line and established the mtG4-ChIP method, enabling the determination of mtDNA G4s under different cellular conditions. Our results are indicative of transient mtDNA G4 formation in human cells. We demonstrate that mtDNA-specific replication stalling increases formation of G4s, particularly in the major arc. Moreover, elevated levels of G4 block the progression of the mtDNA replication fork and cause mtDNA loss. We conclude that stalling of the mtDNA replisome enhances mtDNA G4 occurrence, and that G4s not resolved in a timely manner can have a negative impact on mtDNA integrity.

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  • 8.
    Doimo, Mara
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pfeiffer, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wanrooij, Paulina H.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Umeå University.
    MtDNA replication, maintenance, and nucleoid organization2020Ingår i: The human mitochondrial genome: from basic biology to disease / [ed] Giuseppe Gasparre; Anna Maria Porcelli, Academic Press, 2020, s. 3-33Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Part of the genetic information in human cells resides in the mitochondria. Faithful maintenance of mitochondrial deoxyribonucleic acid (mtDNA) is crucial for the oxidative phosphorylation system that produces the majority of the cellular ATP, and therefore to life. This chapter provides an introduction into the characteristics of human mtDNA and summarizes the processes and factors required for the replication and maintenance of this small but essential genome. We also describe the organization of mtDNA in specialized nucleoprotein structures called nucleoids. Where applicable, we refer to human disease states that are caused by defects in the described factors or processes.

  • 9. Fonseca, Luis Vazquez
    et al.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Clinical Genetics Unit, Department of Women and Children's Health, IRP Città della Speranza, University of Padova, Padova, Italy.
    Calderan, Cristina
    Desbats, Maria Andrea
    Acosta, Manuel J.
    Cerqua, Cristina
    Cassina, Matteo
    Ashraf, Shazia
    Hildebrandt, Friedhelm
    Sartori, Geppo
    Navas, Placido
    Trevisson, Eva
    Salviati, Leonardo
    Mutations in COQ8B (ADCK4) found in patients with steroid-resistant nephrotic syndrome alter COQ8B function2018Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 39, nr 3, s. 406-414Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutations in COQ8B cause steroid-resistant nephrotic syndrome with variable neurological involvement. In yeast, COQ8 encodes a protein required for coenzyme Q (CoQ) biosynthesis, whose precise role is not clear. Humans harbor two paralog genes: COQ8A and COQ8B (previously termed ADCK3 and ADCK4). We have found that COQ8B is a mitochondrial matrix protein peripherally associated with the inner membrane. COQ8B can complement a Delta COQ8 yeast strain when its mitochondrial targeting sequence (MTS) is replaced by a yeast MTS. This model was employed to validate COQ8B mutations, and to establish genotype-phenotype correlations. All mutations affected respiratory growth, but there was no correlation between mutation type and the severity of the phenotype. In fact, contrary to the case of COQ2, where residual CoQ biosynthesis correlates with clinical severity, patients harboring hypomorphic COQ8B alleles did not display a different phenotype compared with those with null mutations. These data also suggest that the system is redundant, and that other proteins (probably COQ8A) may partially compensate for the absence of COQ8B. Finally, a COQ8B polymorphism, present in 50% of the European population (NM_024876.3:c.521A > G, p.His174Arg), affects stability of the protein and could represent a risk factor for secondary CoQ deficiencies or for other complex traits.

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  • 10.
    Jamroskovic, Jan
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chand, Karam
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Obi, Ikenna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kumar, Rajendra
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Brännström, Kristoffer
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Hedenström, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Das, Rabindra Nath
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Akhunzianov, Almaz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia.
    Deiana, Marco
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Kasho, Kazutoshi
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sulis Sato, Sebastian
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Pourbozorgi-Langroudi, Parham
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Mason, James E.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Medini, Paolo
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Öhlund, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Sabouri, Nasim
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization2020Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 142, nr 6, s. 2876-2888Artikel i tidskrift (Refereegranskat)
    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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  • 11.
    Kasho, Kazutoshi
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Stojkovic, Gorazd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    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 universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Laurent, Timothée
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Berner, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    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 universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    A unique arginine cluster in PolDIP2 enhances nucleotide binding and DNA synthesis by PrimPol2021Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 49, nr 4, s. 2179-2191Artikel i tidskrift (Refereegranskat)
    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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  • 12. Montioli, Riccardo
    et al.
    Desbats, Maria Andrea
    Grottelli, Silvia
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik. Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Italy.
    Bellezza, Ilaria
    Voltattorni, Carla Boni
    Salviati, Leonardo
    Cellini, Barbara
    Molecular and cellular basis of ornithine δ-aminotransferase deficiency caused by the V332M mutation associated with gyrate atrophy of the choroid and retina2018Ingår i: Biochimica et Biophysica Acta - Molecular Basis of Disease, ISSN 0925-4439, E-ISSN 1879-260X, Vol. 1864, nr 11, s. 3629-3638Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Gyrate atrophy (GA) is a rare recessive disorder characterized by progressive blindness, chorioretinal degeneration and systemic hyperornithinemia. GA is caused by point mutations in the gene encoding ornithine δ-aminotransferase (OAT), a tetrameric pyridoxal 5′-phosphate-dependent enzyme catalysing the transamination of l-ornithine and α-ketoglutarate to glutamic–γ-semialdehyde and l-glutamate in mitochondria. More than 50 OAT variants have been identified, but their molecular and cellular properties are mostly unknown. A subset of patients is responsive to pyridoxine administration, although the mechanisms underlying responsiveness have not been clarified. Herein, we studied the effects of the V332M mutation identified in pyridoxine-responsive patients. The Val332-to-Met substitution does not significantly affect the spectroscopic and kinetic properties of OAT, but during catalysis it makes the protein prone to convert into the apo-form, which undergoes unfolding and aggregation under physiological conditions. By using the CRISPR/Cas9 technology we generated a new cellular model of GA based on HEK293 cells knock-out for the OAT gene (HEK-OAT_KO). When overexpressed in HEK-OAT_KO cells, the V332M variant is present in an inactive apodimeric form, but partly shifts to the catalytically-competent holotetrameric form in the presence of exogenous PLP, thus explaining the responsiveness of these patients to pyridoxine administration. Overall, our data represent the first integrated molecular and cellular analysis of the effects of a pathogenic mutation in OAT. In addition, we validated a novel cellular model for the disease that could prove instrumental to define the molecular defect of other GA-causing variants, as well as their responsiveness to pyridoxine and other putative drugs.

  • 13.
    Prasad, Bagineni
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Doimo, Mara
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Andréasson, Måns
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    L'Hôte, Valentin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Chorell, Erik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Wanrooij, Sjoerd
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    A complementary chemical probe approach towards customized studies of G-quadruplex DNA structures in live cells2022Ingår i: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 13, nr 8, s. 2347-2354Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    G-quadruplex (G4) DNA structures are implicated in central biological processes and are considered promising therapeutic targets because of their links to human diseases such as cancer. However, functional details of how, when, and why G4 DNA structures form in vivo are largely missing leaving a knowledge gap that requires tailored chemical biology studies in relevant live-cell model systems. Towards this end, we developed a synthetic platform to generate complementary chemical probes centered around one of the most effective and selective G4 stabilizing compounds, Phen-DC3. We used a structure-based design and substantial synthetic devlopments to equip Phen-DC3 with an amine in a position that does not interfere with G4 interactions. We next used this reactive handle to conjugate a BODIPY fluorophore to Phen-DC3. This generated a fluorescent derivative with retained G4 selectivity, G4 stabilization, and cellular effect that revealed the localization and function of Phen-DC3 in human cells. To increase cellular uptake, a second chemical probe with a conjugated cell-penetrating peptide was prepared using the same amine-substituted Phen-DC3 derivative. The cell-penetrating peptide conjugation, while retaining G4 selectivity and stabilization, increased nuclear localization and cellular effects, showcasing the potential of this method to modulate and direct cellular uptake e.g. as delivery vehicles. The applied approach to generate multiple tailored biochemical tools based on the same core structure can thus be used to advance the studies of G4 biology to uncover molecular details and therapeutic approaches. This journal is

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