Shafie, Alaa, Xue, Mingzhan, Barker, Guy C., Zehnder, Daniel, Thornalley, Paul J. and Rabbani, Naila (2016) Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cells in vitro. Biochemical Journal, 473 (22). pp. 4255-4270. doi:10.1042/BCJ20160691

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Abstract

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.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history Q Science > QP Physiology
Divisions:	Faculty of Science > Life Sciences (2010- ) Faculty of Science > Centre for Systems Biology Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH):	Glyoxalase, Embryonic stem cell
Journal or Publication Title:	Biochemical Journal
Publisher:	Portland Press
ISSN:	0264-6021
Official Date:	10 November 2016
Dates:	Date Event 10 November 2016 Published 26 September 2016 Accepted 19 July 2016 Submitted
Date of first compliant deposit:	14 November 2016
Volume:	473
Number:	22
Page Range:	pp. 4255-4270
DOI:	10.1042/BCJ20160691
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Restricted or Subscription Access
Funder:	Saudi Arabia. Wizārat al-Taʻlīm al-ʻĀlī

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