A5010590651- DNA Repair Mechanisms
- Mitochondrial Function and Pathology
- Biochemical and Molecular Research
- Metabolism and Genetic Disorders
- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- Chronic Lymphocytic Leukemia Research
- Genomics and Chromatin Dynamics
- Glycosylation and Glycoproteins Research
- RNA modifications and cancer
- Cancer Genomics and Diagnostics
- Genetic factors in colorectal cancer
- Bacterial Genetics and Biotechnology
- Calcium signaling and nucleotide metabolism
- Probiotics and Fermented Foods
- Plant tissue culture and regeneration
- RNA Research and Splicing
- Bacteriophages and microbial interactions
- Microtubule and mitosis dynamics
- Genomics and Phylogenetic Studies
- DNA and Nucleic Acid Chemistry
- Cancer therapeutics and mechanisms
- Gut microbiota and health
- Genetics and Neurodevelopmental Disorders
- Mycobacterium research and diagnosis
University of Gothenburg
2017-2023
Institute for Biomedicine
2019
Chr. Hansen (Denmark)
2015-2017
Lund University
2006-2016
National Institute of Environmental Health Sciences
2012-2015
National Institutes of Health
2013-2015
Mutational heterogeneity must be taken into account when reconstructing evolutionary histories, calibrating molecular clocks, and predicting links between genes disease. Selective pressures various DNA transactions have been invoked to explain the heterogeneous distribution of genetic variation species, within populations, in tissue-specific tumors. To examine relationships such variations leading- lagging-strand replication fidelity mismatch repair, we accumulated 40,000 spontaneous...
Sequencing of whole cancer genomes has revealed an abundance recurrent mutations in gene-regulatory promoter regions, particular melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these commonly believed be due locally inhibited DNA repair. Here, we first show that low-dose UV light induces preferably at a known ETS hotspot cultured cells even the absence global or...
Previous work has demonstrated the presence of ribonucleotides in human mitochondrial DNA (mtDNA) and present study we use a genome-wide approach to precisely map location these. We find that are distributed evenly between heavy- light-strand mtDNA. The relative levels incorporated reflect polymerase γ discriminates four differentially during synthesis. observed pattern is also dependent on deoxyribonucleotide (dNTP) pools disease-causing mutations change these alter both absolute...
Human mitochondrial DNA (mtDNA) replication is first initiated at the origin of H-strand replication. The initiation depends on RNA primers generated by transcription from an upstream promoter (LSP). Here we reconstitute this process in vitro using purified and factors. majority all events LSP are prematurely terminated after ~120 nucleotides, forming stable R-loops. These nascent R-loops cannot directly prime mtDNA synthesis, but must be processed RNase H1 to generate 3′-ends that can used...
Incorporation of ribonucleotides into DNA during genome replication is a significant source genomic instability. The frequency in determined by deoxyribonucleoside triphosphate/ribonucleoside triphosphate (dNTP/rNTP) ratios, the ability polymerases to discriminate against ribonucleotides, and capacity repair mechanisms remove incorporated ribonucleotides. To simultaneously compare how nuclear mitochondrial genomes incorporate we challenged these processes changing balance cellular dNTPs....
To investigate the bactericidal activity of antiviral and anticancer nucleoside analogues against a variety pathogenic bacteria characterize activating enzymes, deoxyribonucleoside kinases (dNKs). Several FDA-approved analogue drugs were screened for their potential several clinical bacterial isolates type strains. We identified subcloned genes coding putative in Escherichia coli, Pasteurella multocida, Salmonella enterica, Yersinia enterocolitica, Bacillus cereus, Clostridium perfringens...
Significance More than a million ribonucleotides may be incorporated into the mammalian nuclear genome during each round of DNA replication. When these are not removed, they persist in template used for next Here we show that replicases stall when attempting to bypass templates, with stalling increasing as number consecutive increases from one four. Structural analysis reveals is associated displacement conserved tyrosine residue important strand interactions and an unpreferred C2´-endo...
Common bacterial pathogens are becoming progressively more resistant to traditional antibiotics, representing a major public-health crisis. Therefore, there is need for variety of antibiotics with alternative modes action. In our study, several nucleoside analogs were tested against pathogenic staphylococci and streptococci. We show that pyrimidine-based analogs, like 3'-azido-3'-deoxythymidine (AZT) 2',2'-difluoro-2'deoxycytidine (gemcitabine), specifically activated by the endogenous...
Deoxyribonucleotides are the building blocks of DNA and can be synthesized via de novo salvage pathways. Deoxyribonucleoside kinases ( EC 2.7.1.145 ) deoxyribonucleosides by transfer a phosphate group to 5′ deoxyribonucleoside. This pathway is well characterized in mammals, but contrast, little known about how plants deoxyribonucleosides. We show that during salvage, phosphorylated extracts A rabidopsis thaliana into corresponding monophosphate compounds with an unexpected preference for...
Abstract The in vivo role for RNase H1 mammalian mitochondria has been much debated. Loss of is embryonic lethal and to further study its mtDNA expression we characterized a conditional knockout Rnaseh1 mouse heart. We report that essential processing RNA primers allow site-specific initiation replication. Without H1, the RNA:DNA hybrids at replication origins are not processed initiated non-canonical sites becomes impaired. Importantly, also needed completion absence linear deleted...
Abstract Fruit fly ( Drosophila melanogaster ) deoxyribonucleoside kinase Dm dNK; EC: 2.7.1.145) was characterized for its substrate specificity towards natural and non‐natural nucleosides, confirming potential in the enzymatic synthesis of modified nucleotides. dNK adsorbed on a solid ion exchange support (bearing primary amino groups) achieving an expressed activity >98%. Upon cross‐linking with aldehyde dextran, 30‐40%. Both biocatalysts (adsorbed or cross‐linked) were stable at pH 10...
The aim of this study was to investigate the effect altering fatty acid profile lipid membrane on storage survival freeze‐dried probiotic, Lactobacillus acidophilus La‐5, as well integrity and oxidation. composition L. La‐5 significantly different upon growth in MRS (containing Tween 80, an oleic source), or with 20 C12:0 C14:0), linoleic, linolenic supplemented. Bacteria grown showed highest rates. No indications loss could be found, therefore not connected viability. Survival bacteria...
Ribonucleotides (rNMPs) incorporated in the nuclear genome are a well-established threat to stability and can result DNA strand breaks when not removed timely manner. However, presence of certain level rNMPs is tolerated mitochondrial (mtDNA) although aberrant mtDNA rNMP content has been identified disease models. We investigated effect on over mouse life span found that increased during early life. The varied greatly across different tissues was defined by rNTP/dNTP ratio tissue....
The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as nucleoside analog, into cytotoxic compound. Although this therapeutic strategy has been considered promising regimen central nervous system (CNS) tumors, several obstacles have encountered inefficient transfer to tumor cells, limited prodrug penetration CNS, activity gene. We report here cloning successful application...
DNA polymerase η (pol η) is best known for its ability to bypass UV-induced thymine-thymine (T-T) dimers and other bulky lesions, but pol also has cellular roles. Here, we present evidence that competes with polymerases α δ the synthesis of lagging strand genome-wide, where it shows a preference T-T in template. Moreover, found C-terminus η, which contains PCNA-Interacting Protein motif required function synthesis. Finally, provide dependent signature be specific patients skin cancer. Taken...
Abstract Thymidine kinases (TKs) appear to be almost ubiquitous and are found in nearly all prokaryotes, eukaryotes, several viruses. They the key enzymes thymidine salvage activation of anti-cancer antiviral drugs. We show that bacterial TKs can subdivided into 2 groups. The from Gram-positive bacteria more closely related eukaryotic TK1 than Gram-negative bacteria. Keywords: kinaseDeoxyribonucleoside kinaseNucleosidesPyrimidinesEvolutionNucleic acids precursors Acknowledgments work...
Abstract In Escherichia coli, replication of both strands genomic DNA is carried out by a single replicase—DNA polymerase III holoenzyme (pol HE). However, in certain genetic backgrounds, the low-fidelity TLS polymerase, V V) gains access to undamaged where it promotes elevated levels spontaneous mutagenesis preferentially on lagging strand. We employed active site mutants pol IIIα_S759N) and V_Y11A) analyze ribonucleotide incorporation removal from E. coli chromosome genome-wide scale under...
Thymidine kinase (TK) is the key enzyme in salvaging thymidine to produce monophosphate. Owing its ability phosphorylate nucleoside analogue prodrugs, TK has gained attention as a rate‐limiting drug activator. We describe structures of two bacterial TKs, one from pathogen Bacillus anthracis complex with substrate dT, and second food‐poison‐associated cereus feedback inhibitor dTTP. Interestingly, contrast previous dTTP, this study dTTP occupies phosphate donor site not acceptor site. This...
An industrial scale biomass production using batch or fed‐batch fermentations usually optimized by selection of bacterial strains, tuning fermentation media, feeding strategy, and temperature. However, in‐depth investigation the metabolome during may reveal new knowledge for better optimization. In this study, first time, authors investigated seven batches performed on five Streptoccoccus thermophilus strains at Chr. Hansen (Denmark) in a real life large process. The study is designed to...