Glyoxalase 1 (Glo1) is a cytoplasmic enzyme with a cytoprotective function linked to metabolism of the cytotoxic side product of glycolysis, methylglyoxal (MG). It prevents dicarbonyl stress — the abnormal accumulation of reactive dicarbonyl metabolites, increasing protein and DNA damage. Increased Glo1 expression delays ageing and suppresses carcinogenesis, insulin resistance, cardiovascular disease and vascular complications of diabetes and renal failure. Surprisingly, gene trapping by the International Mouse Knockout Consortium (IMKC) to generate putative Glo1 knockout mice produced a mouse line with the phenotype characterised as normal and healthy. Here, we show that gene trapping mutation was successful, but the presence of Glo1 gene duplication, probably in the embryonic stem cells (ESCs) before gene trapping, maintained wild-type levels of Glo1 expression and activity and sustained the healthy phenotype. In further investigation of the consequences of dicarbonyl stress in ESCs, we found that prolonged exposure of mouse ESCs in culture to high concentrations of MG and/or hypoxia led to low-level increase in Glo1 copy number. In clinical translation, we found a high prevalence of low-level GLO1 copy number increase in renal failure where there is severe dicarbonyl stress. In conclusion, the IMKC Glo1 mutant mouse is not deficient in Glo1 expression through duplication of the Glo1 wild-type allele. Dicarbonyl stress and/or hypoxia induces low-level copy number alternation in ESCs. Similar processes may drive rare GLO1 duplication in health and disease.
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November 2016
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Cover Image
Photomontage from Drosophila wing and halter imaginal discs in different color combinations that were stained using antibodies against blistered-lacZ reporter, Cubitus interruptus and Notch target gene cut; cell nuclei were visualised by DAPI staining. This is a result of an experiment related to a paper on pp. 4129–4143. Picture taken and provided by Raquel Perez-Gomez.
Research Article|
November 10 2016
Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cells in vitro
Alaa Shafie;
Alaa Shafie
1Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry CV2 2DX, U.K.
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Mingzhan Xue;
Mingzhan Xue
1Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry CV2 2DX, U.K.
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Guy Barker;
Guy Barker
2School of Life Sciences, University of Warwick, Wellesbourne CV35 9EF, U.K.
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Daniel Zehnder;
Daniel Zehnder
1Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry CV2 2DX, U.K.
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Paul J. Thornalley;
Paul J. Thornalley
†
1Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry CV2 2DX, U.K.
3Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry CV4 7AL, U.K.
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Naila Rabbani
Naila Rabbani
1Warwick Medical School, Clinical Sciences Research Laboratories, University of Warwick, University Hospital, Coventry CV2 2DX, U.K.
3Warwick Systems Biology Centre, Senate House, University of Warwick, Coventry CV4 7AL, U.K.
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Publisher: Portland Press Ltd
Received:
July 19 2016
Revision Received:
September 21 2016
Accepted:
September 26 2016
Accepted Manuscript online:
September 26 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (22): 4255–4270.
Article history
Received:
July 19 2016
Revision Received:
September 21 2016
Accepted:
September 26 2016
Accepted Manuscript online:
September 26 2016
Citation
Alaa Shafie, Mingzhan Xue, Guy Barker, Daniel Zehnder, Paul J. Thornalley, Naila Rabbani; Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cells in vitro. Biochem J 15 November 2016; 473 (22): 4255–4270. doi: https://doi.org/10.1042/BCJ20160691
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