Ligase 3-mediated end-joining maintains genome stability of human embryonic stem cells

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Authors

KOHUTOVÁ Aneta RAŠKA Jan KRUTÁ Miriama ŠENEKLOVÁ Monika BÁRTA Tomáš FOJTÍK Petr JURÁKOVÁ Tereza WALTER Christi A. HAMPL Aleš DVOŘÁK Petr ROTREKL Vladimír

Year of publication 2019
Type Article in Periodical
Magazine / Source Faseb Journal
MU Faculty or unit

Faculty of Medicine

Citation
Web http://dx.doi.org/10.1096/fj.201801877RR
Doi http://dx.doi.org/10.1096/fj.201801877RR
Keywords base excision repair; PARP1; 53BP1; pluripotent stem cells; alternative DNA end-joining
Description 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., Raska, 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.
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