6 results on '"Diana L. Bordin"'
Number of results to display per page
Search Results
2. Increased p53 signaling impairs neural differentiation in HUWE1-promoted intellectual disabilities
- Author
-
Rossana Aprigliano, Merdane Ezgi Aksu, Stefano Bradamante, Boris Mihaljevic, Wei Wang, Kristin Rian, Nicola P. Montaldo, Kayla Mae Grooms, Sarah L. Fordyce Martin, Diana L. Bordin, Matthias Bosshard, Yunhui Peng, Emil Alexov, Cindy Skinner, Nina-Beate Liabakk, Gareth J. Sullivan, Magnar Bjørås, Charles E. Schwartz, and Barbara van Loon
- Subjects
X-linked intellectual disability ,E3 ubiquitin ligase ,HUWE1 ,p53 ,neurodevelopment ,Medicine (General) ,R5-920 - Abstract
Summary: Essential E3 ubiquitin ligase HUWE1 (HECT, UBA, and WWE domain containing 1) regulates key factors, such as p53. Although mutations in HUWE1 cause heterogenous neurodevelopmental X-linked intellectual disabilities (XLIDs), the disease mechanisms common to these syndromes remain unknown. In this work, we identify p53 signaling as the central process altered in HUWE1-promoted XLID syndromes. By focusing on Juberg-Marsidi syndrome (JMS), one of the severest XLIDs, we show that increased p53 signaling results from p53 accumulation caused by HUWE1 p.G4310R destabilization. This further alters cell-cycle progression and proliferation in JMS cells. Modeling of JMS neurodevelopment reveals majorly impaired neural differentiation accompanied by increased p53 signaling. The neural differentiation defects can be successfully rescued by reducing p53 levels and restoring the expression of p53 target genes, in particular CDKN1A/p21. In summary, our findings suggest that increased p53 signaling underlies HUWE1-promoted syndromes and impairs XLID JMS neural differentiation.
- Published
- 2021
- Full Text
- View/download PDF
3. Biological functions of selenium and its potential influence on Parkinson's disease
- Author
-
JOEL H. ELLWANGER, SILVIA I.R. FRANKE, DIANA L. BORDIN, DANIEL PRÁ, and JOÃO A.P. HENRIQUES
- Subjects
neurodegeneração ,nutrição ,estresse oxidativo ,doença de Parkinson ,selênio ,Science - Abstract
ABSTRACT Parkinson's disease is characterized by the death of dopaminergic neurons, mainly in the substantia nigra, and causes serious locomotor dysfunctions. It is likely that the oxidative damage to cellular biomolecules is among the leading causes of neurodegeneration that occurs in the disease. Selenium is an essential mineral for proper functioning of the brain, and mainly due to its antioxidant activity, it is possible to exert a special role in the prevention and in the nutritional management of Parkinson's disease. Currently, few researchers have investigated the effects of selenium on Parkinson´s disease. However, it is known that very high or very low body levels of selenium can (possibly) contribute to the pathogenesis of Parkinson's disease, because this imbalance results in increased levels of oxidative stress. Therefore, the aim of this work is to review and discuss studies that have addressed these topics and to finally associate the information obtained from them so that these data and associations serve as input to new research.
- Published
- 2016
- Full Text
- View/download PDF
4. Alkyladenine DNA glycosylase deficiency uncouples alkylation-induced strand break generation from PARP-1 activation and glycolysis inhibition
- Author
-
Larissa Milano, Ruan M. Elliott, Izabel Vianna Villela, Kathryn E. Plant, Michael D. McNicholas, Clara F. Charlier, Fahad A. Alhumaydhi, Lisiane B. Meira, Diana L. Bordin, João Antonio Pêgas Henriques, Abdullah S. M. Aljohani, Cameron B. Lloyd, and Débora de Oliveira Lopes
- Subjects
Alkylation ,DNA Repair ,DNA repair ,Poly ADP ribose polymerase ,Primary Cell Culture ,Nicotinamide phosphoribosyltransferase ,Poly (ADP-Ribose) Polymerase-1 ,lcsh:Medicine ,Biochemistry ,Article ,DNA Glycosylases ,chemistry.chemical_compound ,Glycolysis Inhibition ,Mice ,Piperidines ,polycyclic compounds ,Animals ,lcsh:Science ,Nicotinamide Phosphoribosyltransferase ,Cells, Cultured ,Mice, Knockout ,Acrylamides ,Multidisciplinary ,lcsh:R ,DNA Breaks ,Base excision repair ,DNA ,Fibroblasts ,Methyl Methanesulfonate ,NAD ,female genital diseases and pregnancy complications ,Methyl methanesulfonate ,Cell biology ,DNA Alkylation ,chemistry ,Cytokines ,lcsh:Q ,NAD+ kinase ,Glycolysis - Abstract
DNA alkylation damage is repaired by base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG). Despite its role in DNA repair, AAG-initiated BER promotes cytotoxicity in a process dependent on poly (ADP-ribose) polymerase-1 (PARP-1); a NAD+-consuming enzyme activated by strand break intermediates of the AAG-initiated repair process. Importantly, PARP-1 activation has been previously linked to impaired glycolysis and mitochondrial dysfunction. However, whether alkylation affects cellular metabolism in the absence of AAG-mediated BER initiation is unclear. To address this question, we temporally profiled repair and metabolism in wild-type and Aag−/− cells treated with the alkylating agent methyl methanesulfonate (MMS). We show that, although Aag−/− cells display similar levels of alkylation-induced DNA breaks as wild type, PARP-1 activation is undetectable in AAG-deficient cells. Accordingly, Aag−/− cells are protected from MMS-induced NAD+ depletion and glycolysis inhibition. MMS-induced mitochondrial dysfunction, however, is AAG-independent. Furthermore, treatment with FK866, a selective inhibitor of the NAD+ salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT), synergizes with MMS to induce cytotoxicity and Aag−/− cells are resistant to this combination FK866 and MMS treatment. Thus, AAG plays an important role in the metabolic response to alkylation that could be exploited in the treatment of conditions associated with NAD+ dysregulation.
- Published
- 2020
5. Alkyladenine DNA glycosylase associates with transcription elongation to coordinate DNA repair with gene expression
- Author
-
Diana L. Bordin, Per Arne Aas, Marit Otterlei, Alessandro Brambilla, Nicolas Kunath, Magnar Bjørås, Antonia Furrer, Sarah L. Fordyce Martin, Stefano Bradamante, Pål Sætrom, Nicola P. Montaldo, Karine Øian Bjørås, Lene Christin Olsen, Barbara van Loon, Leona D. Samson, and Marcel Rösinger
- Subjects
0301 basic medicine ,Genome instability ,Transcription Elongation, Genetic ,DNA Repair ,DNA repair ,Science ,General Physics and Astronomy ,Gene Expression ,RNA polymerase II ,General Biochemistry, Genetics and Molecular Biology ,Article ,Genomic Instability ,DNA Glycosylases ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,RNA polymerase ,DNA-(Apurinic or Apyrimidinic Site) Lyase ,Humans ,lcsh:Science ,Gene ,Base excision repair ,Multidisciplinary ,biology ,General Chemistry ,DNA ,DNA Methylation ,Chromatin ,Cell biology ,030104 developmental biology ,HEK293 Cells ,chemistry ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,DNA methylation ,biology.protein ,lcsh:Q ,RNA Polymerase II ,Transcriptional Elongation Factors - Abstract
Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases, including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here, we show that AAG binds to chromatin and forms complex with RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation. Importantly, at co-regulated genes, aberrantly methylated bases accumulate towards the 3′end in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide insights into genome stability maintenance in actively transcribing chromatin and reveal roles of aberrantly methylated bases in regulation of gene expression., How genome stability is maintained at regions of active transcription is currently not entirely clear. Here, the authors reveal an association between base excision repair factors and transcription elongation to modulate DNA repair.
- Published
- 2019
6. Rapid genome editing by CRISPR-Cas9-POLD3 fusion
- Author
-
Ganna Reint, Zhuokun Li, Kornel Labun, Salla Keskitalo, Inkeri Soppa, Katariina Mamia, Eero Tolo, Monika Szymanska, Leonardo A Meza-Zepeda, Susanne Lorenz, Artur Cieslar-Pobuda, Xian Hu, Diana L Bordin, Judith Staerk, Eivind Valen, Bernhard Schmierer, Markku Varjosalo, Jussi Taipale, and Emma Haapaniemi
- Subjects
CRISPR-Cas9 ,gene editing ,molecular biology ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Precision CRISPR gene editing relies on the cellular homology-directed DNA repair (HDR) to introduce custom DNA sequences to target sites. The HDR editing efficiency varies between cell types and genomic sites, and the sources of this variation are incompletely understood. Here, we have studied the effect of 450 DNA repair protein-Cas9 fusions on CRISPR genome editing outcomes. We find the majority of fusions to improve precision genome editing only modestly in a locus- and cell-type specific manner. We identify Cas9-POLD3 fusion that enhances editing by speeding up the initiation of DNA repair. We conclude that while DNA repair protein fusions to Cas9 can improve HDR CRISPR editing, most need to be optimized to the cell type and genomic site, highlighting the diversity of factors contributing to locus-specific genome editing outcomes.
- Published
- 2021
- Full Text
- View/download PDF
Catalog
Books, media, physical & digital resources
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.