Research Theme within School of Biosciences: Molecular and Cell Biology - Toxicology
We are interested in the cellular consequences of pertubation of redox homeostasis both by chemical and biological mechanisms.
OGG1: The DNA repair protein OGG1 is critical in the repair of the oxidatively damaged base 8 oxo dG which if not removed before DNA replication mispairs with adenine and thymine causing point mutations. We are interested in the common ser326cys polymorphism in human OGG1 and are studying its activity and location compared to the “normal” protein. Work in our lab using genetically engineered cell lines has shown that the variant form of the protein is repair deficient particularly under conditions of cellular oxidative stress when it is needed most and we are currently studying the mechanistic basis for this observation.
Cellular oxidative stress: We are using a number of experimental approaches to study the consequences of intracellular oxidative stress: These include treatment with pro-oxidants, tungsten alloys, engineered nanoparticles, depletion of the protective factor glutathione and over-expression of cytochrome P450s for which there is evidence that once “un-coupled” for example by futile substrates like polychlorinated chemicals these enzyme systems can generate substantial level of toxic free radicals in cells. We are particularly interested in oxidative DNA damage through so called “secondary genotoxicity” and the existence of potential thresholds of effect in relation to these mechanisms of toxicity.
Cytoglobin: We are interested in cytoglobin a poorly understood homologue of haemoglobin with no known function but which may be involved in detoxification of reactive oxygen species as well as having signalling and oxygen transporter functions in a wide range of non muscle tissues especially those of a fibroblast lineage. Through collaboration with AstraZeneca were are studying the role of cytoglobin in fibrotic disease and as a potential target for drug toxicity. The cytoglobin gene also maps to a genetic disease called tylosis with oesphageal cancer (TOC) and in collaboration with The University of Liverpool we are working on the genetic regulation of this gene and trying to determine its molecular function.
Iron cylinders: In collaboration with Professors Mike Hannon and Kevin Chipman we are investigating the cellular properties of iron and related cylinders which have potent cytostatic effects in a broad range of cell lines. You can read more about these exciting molecules on the homepage of Professor Mike Hannon http://www.chem.bham.ac.uk/staff/hannon.shtml.
Example publications from the Hodges lab:
Kershaw RM and Hodges NJ. (2011) Repair of oxidative DNA damage is delayed in the Ser326Cys polymorphic variant of the base excision repair protein OGG1. Submitted to PLoS1
Zielinska A, Davies OT, Meldrum RA, Hodges NJ. Direct visualization of repair of oxidative damage by OGG1 in the nuclei of live cells. J Biochem Mol Toxicol. 2011 Jan-Feb;25(1):1-7.
Mirbahai L, Kershaw RM, Green RM, Hayden RE, Meldrum RA, Hodges NJ. Use of a molecular beacon to track the activity of base excision repair protein OGG1 in live cells. DNA Repair (Amst). 2010 Feb 4;9(2):144-52. Epub 2009 Dec 29.
Smart DJ, Chipman JK, Hodges NJ. Activity of OGG1 variants in the repair of pro-oxidant-induced 8-oxo-2'-deoxyguanosine. DNA Repair (Amst). 2006 Nov 8;5(11):1337-45
Lee AJ, Hodges NJ, Chipman JK. Interindividual variability in response to sodium dichromate-induced oxidative DNA damage: role of the Ser326Cys polymorphism in the DNA-repair protein of 8-oxo-7,8- dihydro-2'- deoxy- guanosine DNA glycosylase 1. Cancer Epidemiol Biomarkers Prev. 2005 Feb;14(2):497-505.
Hodges NJ, Chipman JK. Down-regulation of the DNA-repair endonuclease 8-oxo-guanine DNA glycosylase 1 (hOGG1) by sodium dichromate in cultured human A549 lung carcinoma cells. Carcinogenesis. 2002 Jan;23(1):55-60.
Oxidative stress related
Robert M Harris, Nikolas J Hodges and Rosemary M Waring. Reactive oxygen species and oxidative DNA damage mediate the cytotoxicity of tungsten-nickel-cobalt alloys in vitro. 2010 Toxicology and Applied Pharmacology Available online October 8th 2010. doi:10.1016/j.taap.2010.09.020.
Priestley CC, Green RM, Fellows MD, Doherty AT, Hodges NJ, O'Donovan MR. Anomalous genotoxic responses induced in mouse lymphoma L5178Y cells by potassium bromate. Toxicology. 2010 Jan 12;267(1-3):45-53.
Green RM, Hodges NJ, Chipman JK, O'Donovan MR, Graham M. Reactive oxygen species from the uncoupling of human cytochrome P450 1B1 may contribute to the carcinogenicity of dioxin-like polychlorinated biphenyls. Mutagenesis. 2008 Nov;23(6):457-63. Epub 2008 Jun 26.
Hodges NJ, Green RM, Chipman JK, Graham M. Induction of DNA strand breaks and oxidative stress in HeLa cells by ethanol is dependent on CYP2E1 expression. Mutagenesis. 2007 May;22(3):189-94.
Green RM, Graham M, O'Donovan MR, Chipman JK, Hodges NJ. Subcellular compartmentalization of glutathione: correlations with parameters of oxidative stress related to genotoxicity. Mutagenesis. 2006 Nov;21(6):383-90
Lee AJ, Hodges NJ, Chipman JK. Modified comet assay as a biomarker of sodium dichromate-induced oxidative DNA damage: optimization and reproducibility. Biomarkers. 2004 Mar-Apr;9(2):103-15.
Hodges NJ, Smart D, Lee AJ, Lewis NA, Chipman JK. Activation of c-Jun N-terminal kinase in A549 lung carcinoma cells by sodium dichromate: role of dissociation of apoptosis signal regulating kinase-1 from its physiological inhibitor thioredoxin. Toxicology. 2004 Apr 15;197(2):101-12.
Hodges NJ, Orton TC, Strain AJ, Chipman JK. Potentiation of epidermal growth factor-induced DNA synthesis in rat hepatocytes by phenobarbitone: possible involvement of oxidative stress and kinase activation. Carcinogenesis. 2000 Nov;21(11):2041-7.
Cardo L, Sadovnikova V, Phongtongpasuk S, Hodges NJ, Hannon MJ. Arginine conjugates of metallo-supramolecular cylinders prescribe helicity and enhance DNA junction binding and cellular activity. Chem Commun (Camb). 2011 Jun 21;47(23):6575-
Cosimo Ducani, Anna Leczkowska, Nikolas J. Hodges#, Michael J. Hannon#. Non-Covalent DNA-Binding Metallo-Supramolecular Cylinders Prevent DNA Transactions in vitro. Angewandte Chemie International edition. Article first published online: 8 OCT 2010 DOI: 10.1002/anie.201004471. # Corresponding Authors
Hotze AC+, Hodges NJ+, Hayden RE, Sanchez-Cano C, Paines C, Male N, Tse MK, Bunce CM, Chipman JK, Hannon MJ. Supramolecular iron cylinder with unprecedented DNA binding is a potent cytostatic and apoptotic agent without exhibiting genotoxicity. Chem Biol. 2008 Dec 22;15(12):1258-67. +Joint first authors.
Hodges NJ, Innocent N, Dhanda S, Graham M. Cellular protection from oxidative DNA damage by over-expression of the novel globin cytoglobin in vitro. Mutagenesis. 2008 Jul;23(4):293-8. Epub 2008 Mar 18.