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

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Aneta KohutovaVladimir Rotrekl

Abstract

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 nonhomo...Continue Reading

References

Mar 1, 1997·Critical Reviews in Toxicology·S VamvakasW K Lutz
Jul 22, 1997·Proceedings of the National Academy of Sciences of the United States of America·Y GuF W Alt
Aug 11, 1998·Trends in Biochemical Sciences·P Baumann, S C West
Nov 6, 1998·Science·J A ThomsonJ M Jones
Jan 5, 2000·Proceedings of the National Academy of Sciences of the United States of America·B M SutherlandJ Laval
Mar 14, 2002·Proceedings of the National Academy of Sciences of the United States of America·Rachel B CervantesPeter J Stambrook
Aug 20, 2005·Free Radical Biology & Medicine·Paula V BennettBetsy M Sutherland
Sep 6, 2005·Mutation Research·Graham C Walker
Sep 6, 2005·Nature Genetics·Anirban MaitraAravinda Chakravarti
Feb 8, 2006·The Journal of Experimental Medicine·Myriam CuadradoOscar Fernandez-Capetillo
Sep 15, 2006·Journal of Cellular Physiology·Klaus A BeckerGary S Stein
Feb 9, 2007·Nature Biotechnology·Duncan E C BakerPeter W Andrews
Jun 19, 2007·Nature Biotechnology·UNKNOWN International Stem Cell InitiativeWeidong Zhang
Oct 16, 2007·Nature Structural & Molecular Biology·Katsuhiro HanadaRoland Kanaar
Dec 14, 2007·Molecular BioSystems·Alexandros G Georgakilas
Apr 23, 2008·Current Protocols in Human Genetics·J German, B Alhadeff
Apr 18, 2009·Journal of Cellular Physiology·Tera M FilionGary S Stein
Apr 30, 2009·Nucleic Acids Research·Aroumougame Asaithamby, David J Chen
May 25, 2010·Stem Cells and Development·Lourdes SerranoJay A Tischfield
Jun 15, 2010·Environmental and Molecular Mutagenesis·Pingfang Liu, Bruce Demple
Oct 23, 2010·Molecular Cell·Alberto Ciccia, Stephen J Elledge
Sep 8, 2011·Proceedings of the National Academy of Sciences of the United States of America·Isabella M TollerAnne Müller
Aug 28, 2012·Molecular Cell·J Ross ChapmanSimon J Boulton
Jan 12, 2013·Science·Michal ZimmermannTitia de Lange

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Checkpoints & Regulators

Cell cycle checkpoints are a series of complex checkpoint mechanisms that detect DNA abnormalities and ensure that DNA replication and repair are complete before cell division. They are primarily regulated by cyclins, cyclin-dependent kinases, and the anaphase-promoting complex/cyclosome. Here is the latest research.