Ligase 3-mediated end-joining maintains genome stability of human embryonic stem cells
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- 53BP1, PARP1, alternative DNA end-joining, base excision repair, pluripotent stem cells,
- MeSH
- DNA Ligase ATP genetics metabolism MeSH
- DNA Breaks, Double-Stranded radiation effects MeSH
- Homologous Recombination MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Human Embryonic Stem Cells cytology physiology MeSH
- Genomic Instability * MeSH
- DNA End-Joining Repair physiology radiation effects MeSH
- DNA Repair physiology radiation effects MeSH
- Poly-ADP-Ribose Binding Proteins genetics metabolism MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- DNA Ligase ATP MeSH
- LIG3 protein, human MeSH Browser
- Poly-ADP-Ribose Binding Proteins MeSH
Maintenance of human embryonic stem cells (hESCs) with stable genome is important for their future use in cell replacement therapy and disease modeling. Our understanding of the mechanisms maintaining genomic stability of hESC and our ability to modulate them is essential in preventing unwanted mutation accumulation during their in vitro cultivation. In this study, we show the DNA damage response mechanism in hESCs is composed of known, yet unlikely components. Clustered oxidative base damage is converted into DNA double-strand breaks (DSBs) by base excision repair (BER) and then quickly repaired by ligase (Lig)3-mediated end-joining (EJ). If there is further induction of clustered oxidative base damage by irradiation, then BER-mediated DSBs become essential in triggering the checkpoint response in hESCs. hESCs limit the mutagenic potential of Lig3-mediated EJ by DNA break end protection involving p53 binding protein 1 (53BP1), which results in fast and error-free microhomology-mediated repair and a low mutant frequency in hESCs. DSBs in hESCs are also repaired via homologous recombination (HR); however, DSB overload, together with massive end protection by 53BP1, triggers competition between error-free HR and mutagenic nonhomologous EJ.-Kohutova, A., Raška, J., Kruta, M., Seneklova, M., Barta, T., Fojtik, P., Jurakova, T., Walter, C. A., Hampl, A., Dvorak, P., Rotrekl, V. Ligase 3-mediated end-joining maintains genome stability of human embryonic stem cells.
Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic
Department of Histology and Embryology Faculty of Medicine Masaryk University Brno Czech Republic
International Clinical Research Center St Anne's University Hospital Brno Czech Republic
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