Publications & Prizes

Biochemistry Department Honour Board

Awards given to Department Members

Publications on this page begin in 2012. Some staff have a record of earlier publications on their personal pages.

  • The role of peroxiredoxin 1 in redox sensing and transducing.
  • Elizabeth C Ledgerwood, James W A Marshall, and Johannes F Weijman., Archives of Biochemistry and Biophysics 2016.
  • Published:15 October 2016
  • Peroxiredoxin 1 is a member of the ubiquitous peroxiredoxin family of thiol peroxidases that catalyse the reduction of peroxides. In recent years eukaryotic peroxiredoxins have emerged as a critical component of cellular redox signalling, particularly in response to alterations in production of hydrogen peroxide. Peroxiredoxins are exquisitely sensitive to oxidation by hydrogen peroxide making them key peroxide sensing enzymes within cells. Evidence gathered over the last decade suggests that in addition to sensing the redox signal, peroxiredoxins have a major role in transducing this signal to downstream signalling proteins, ultimately contributing to regulation of diverse cellular processes including proliferation, differentiation and apoptosis. In this review we present the three current models for the sensing and signal transducing roles of peroxiredoxins, with a specific focus on mammalian peroxiredoxin 1. The evidence for each mechanism is discussed and areas for future work are identified.

  • Structural basis for ligand recognition by a Cache chemosensory domain that mediates carboxylate sensing in Pseudomonas syringe.
  • Jodi L Brewster, James L O McKellar, Thomas J Finn, Janet Newman, Thomas S Peat, and Monica L Gerth., Sci Rep 2016 vol. 6 p. 35198.
  • Published:13 October 2016
  • Chemoreceptors enable bacteria to detect chemical signals in the environment and navigate towards niches that are favourable for survival. The sensor domains of chemoreceptors function as the input modules for chemotaxis systems, and provide sensory specificity by binding specific ligands. Cache-like domains are the most common extracellular sensor module in prokaryotes, however only a handful have been functionally or structurally characterised. Here, we have characterised a chemoreceptor Cache-like sensor domain (PscD-SD) from the plant pathogen Pseudomonas syringae pv. actinidiae (Psa). High-throughput fluorescence thermal shift assays, combined with isothermal thermal titration calorimetry, revealed that PscD-SD binds specifically to C2 (glycolate and acetate) and C3 (propionate and pyruvate) carboxylates. We solved the structure of PscD-SD in complex with propionate using X-ray crystallography. The structure reveals the key residues that comprise the ligand binding pocket and dictate the specificity of this sensor domain for C2 and C3 carboxylates. We also demonstrate that all four carboxylate ligands are chemoattractants for Psa, but only two of these (acetate and pyruvate) are utilisable carbon sources. This result suggests that in addition to guiding the bacteria towards nutrients, another possible role for carboxylate sensing is in locating potential sites of entry into the host plant.

  • Uric acid and bone mineral density in postmenopausal osteoporotic women: the link lies within the fat.
  • M Pirro, M R Mannarino, V Bianconi, S De Vuono, A Sahebkar, F Bagaglia, L Franceschini, A M Scarponi, E Mannarino, and T Merriman., Osteoporos Int 2016.
  • Published:10 October 2016
  • The association between serum uric acid (SUA) levels and bone mineral density (BMD) is controversial. Fat accumulation is linked to SUA and BMD, thus possibly explaining the mixed results. We found that adiposity drives part of the association between SUA and BMD in women with postmenopausal osteoporosis.

    INTRODUCTION:Both positive and negative associations between SUA and BMD have been reported. SUA levels and BMD increase with higher body weight and other indices of adiposity; hence, the association between SUA and BMD might be a consequence of the confounding effect of adiposity. We investigated in this cross-sectional study whether the association between SUA and BMD is independent of measures of fat accumulation and other potential confounders.

    METHODS:SUA levels, femur BMD, markers of bone metabolism, body mass index (BMI), fat mass (FM), waist circumference (WC), and abdominal visceral fat area were measured in 180 treatment-naive postmenopausal osteoporotic women (mean age 66.3 ± 8.5 years, age range 48-81 years).

    RESULTS:Women with higher SUA levels (third tertile) had significantly higher femur BMD and lower cross-linked C-terminal telopeptide of type I collagen (CTX) and bone alkaline phosphatase (bALP) levels. SUA levels were positively associated with all indices of adiposity. In multivariable analysis with femur BMD as dependent variable, the association between logarithmic (LG)-transformed SUA levels and BMD (beta = 0.42, p < 0.001) was lessened progressively by the different indices of adiposity, like LG-BMI (beta = 0.22, p = 0.007), LG-WC (beta = 0.21, p = 0.01), LG-FM (beta = 0.18, p = 0.01), and LG-abdominal visceral fat area (beta = 0.12, p = 0.05). The association between SUA levels and markers of bone metabolism was dependent on the effect of confounders.

    CONCLUSION:In postmenopausal osteoporotic women, the strong univariable association between SUA levels and femur BMD is partly explained by the confounding effect of indices of adiposity.

  • Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression.
  • Roberto Rangel, Song-Choon Lee, Kenneth Hon-Kim Ban, Liliana Guzman-Rojas, Michael B Mann, Justin Y Newberg, Takahiro Kodama, Leslie A McNoe, Luxmanan Selvanesan, Jerrold M Ward, Alistair G Rust, Kuan-Yew Chin, Michael A Black, Nancy A Jenkins, and Neal G Copeland., P Natl Acad Sci Usa 2016 p. 201613859.
  • Published:4 October 2016
  • Triple-negative breast cancer (TNBC) has the worst prognosis of any breast cancer subtype. To better understand the genetic forces driving TNBC, we performed a transposon mutagenesis screen in a phosphatase and tensin homolog (Pten) mutant mice and identified 12 candidate trunk drivers and a much larger number of progression genes. Validation studies identified eight TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1 Down-regulation of TRPS1 in TNBC cells promoted epithelial-to-mesenchymal transition (EMT) by deregulating multiple EMT pathway genes, in addition to increasing the expression of SERPINE1 and SERPINB2 and the subsequent migration, invasion, and metastasis of tumor cells. Transposon mutagenesis has thus provided a better understanding of the genetic forces driving TNBC and discovered genes with potential clinical importance in TNBC.

  • Interference-driven spacer acquisition is dominant over naive and primed adaptation in a native CRISPR-Cas system.
  • Raymond H J Staals, Simon A Jackson, Ambarish Biswas, Stan J J Brouns, Chris M Brown, and Peter C. Fineran., Nat Commun 2016 vol. 7 p. 12853.
  • Published:3 October 2016
  • CRISPR-Cas systems provide bacteria with adaptive immunity against foreign nucleic acids by acquiring short, invader-derived sequences called spacers. Here, we use high-throughput sequencing to analyse millions of spacer acquisition events in wild-type populations of Pectobacterium atrosepticum. Plasmids not previously encountered, or plasmids that had escaped CRISPR-Cas targeting via point mutation, are used to provoke naive or primed spacer acquisition, respectively. The origin, location and order of spacer acquisition show that spacer selection through priming initiates near the site of CRISPR-Cas recognition (the protospacer), but on the displaced strand, and is consistent with 3'-5' translocation of the Cas1:Cas2-3 acquisition machinery. Newly acquired spacers determine the location and strand specificity of subsequent spacers and demonstrate that interference-driven spacer acquisition ('targeted acquisition') is a major contributor to adaptation in type I-F CRISPR-Cas systems. Finally, we show that acquisition of self-targeting spacers is occurring at a constant rate in wild-type cells and can be triggered by foreign DNA with similarity to the bacterial chromosome.

  • Phenotypic variation in wild-type substrains of the model cyanobacterium Synechocystis sp. PCC 6803.
  • J N Morris, J. J. Eaton-Rye, and T C Summerfield., New Zeal J Bot 2016 pp. 1-11.
  • Published:3 October 2016
  • © 2016 The Royal Society of New ZealandGenome re-sequencing has revealed numerous genetic differences between wild-type substrains of the model cyanobacterium Synechocystis sp. PCC 6803 held in laboratories around the world. These substrains can be divided into the motile PCC-lineage and non-motile GT-lineage, and frequently display unique genetic mutations that result in residue changes in proteins associated with environmental sensing, gene regulation, cellular transport and photosynthesis. However, despite these findings, phenotypic variation between wild-type substrains does not appear to have been widely reported. In this study, we compared the growth and physiology of three wild-type substrains of Synechocystis sp. PCC 6803, the GT-Kazusa substrain (the source of the original genome sequence for this cyanobacterium), the widely studied PCC-Moscow substrain, and the GT-O1 substrain, in use in our laboratory. We found similarity between all three substrains in terms of growth rate, oxygen evolution and total chlorophyll levels. Although differences in cell size, whole-cell absorption and 77 K fluorescence were observed, the wild-type substrains analysed here are comparable under standard laboratory conditions. 

  • Modular growth vessels for the cultivation of the cyanobacterium Synechococcus sp. PCC 7002.
  • Simon A Jackson and Julian J Eaton-Rye., New Zeal J Bot 2016 pp. 1-11.
  • Published:28 September 2016
  • © 2016 The Royal Society of New ZealandSynechococcus sp. PCC 7002 is a euryhaline cyanobacterium that serves as a model organism for studies of photosynthesis and cellular metabolism. At high light intensity Synechococcus sp. PCC 7002 exhibits a fast growth rate and rapid biomass accumulation, making it an ideal candidate for the production of biofuels and commercially valuable secondary metabolites. To fully realise the production potential for this cyanobacterium a system is required to maintain axenic cultures under optimal growth conditions. We have designed and constructed two sizes of modular culture vessel systems, designed specifically to meet the abnormally high light penetration requirements of Synechococcus sp. PCC 7002. The smaller volume culture vessels are best suited to phenotype analysis, allowing multiple candidate strains to be screened simultaneously, whereas the larger vessels are designed to facilitate higher biomass production.

  • Functional impairment of infiltrating T cells in human colorectal cancer.
  • Edward S Taylor, John L McCall, Adam Girardin, Fran M Munro, Michael A Black, and Roslyn A. Kemp., OncoImmunology 2016 p. e1234573.
  • Published:26 September 2016
  • © 2016 Taylor & Francis Group, LLCT cells play a crucial role in preventing the growth and spread of colorectal cancer (CRC). However, immunotherapies against CRC have only shown limited success, which may be due to lack of understanding about the effect of the local tumor microenvironment (TME) on T cell function. The goal of this study was to determine whether T cells in tumor tissue were functionally impaired compared to T cells in non-tumor bowel (NTB) tissue from the same patients. We showed that T cell populations are affected differently by the TME. In the tumor, T cells produced more IL-17 and less IL-2 per cell than their counterparts from NTB tissue. T cells from tumor tissue also had impaired proliferative ability compared to T cells in NTB tissue. This impairment was not related to the frequency of IL-2 producing T cells or regulatory T cells, but T cells from the TME had a higher co-expression of inhibitory receptors than T cells from NTB. Overall, our data indicate that T cells in tumor tissue are functionally altered by the CRC TME, which is likely due to cell intrinsic factors. The TME is therefore an important consideration in predicting the effect of immune modulatory therapies. 

  • Ribose-Cysteine Increases Glutathione-Based Antioxidant Status and Reduces Atherosclerosis in Apoe-Deficient Mice.
  • S McCormick, T Kader, C Porteous, G Jones, and N Dickerhof., Atherosclerosis 2016 vol. 252 pp. E97-E98.
  • Published:22 September 2016
  • Objectives: Ribose-cysteine is a cysteine analogue designed to increase the synthesis of the cellular antioxidant, glutathione (GSH). Glutathione peroxidase (GPx) requires GSH as a cofactor for the reduction of lipid peroxides. A low GPx activity is associated with an increased risk of developing cardiovascular disease (CVD). We investigated the effect of ribose-cysteine on GSH, GPx, lipid peroxides, plasma lipids and atherosclerosis development in apolipoprotein E-deficient mice (apoE−/− mice).

    Methods: Female apoE−/− mice (12 weeks of age) were treated with 4 mg/day ribose-cysteine in drinking water for 8 weeks (n = 9) or left untreated (n = 9). Blood, livers and aortae were harvested and GSH, GPx activity, F2-isoprostanes and plasma lipid concentrations were measured. Atherosclerotic lesion area in the aortic sinus and brachiocephalic arch of treated and untreated mice were quantified 

    Results: Ribose-cysteine treatment significantly increased GSH concentrations in the liver (p < 0.05) and significantly increased GPx activity in the liver and erythrocytes of apoE−/−mice (p < 0.005). F2-isoprostane levels were significantly reduced in the livers and arteries of apoE−/− mice (p < 0.05 and p < 0.005 respectively). Ribose-cysteine treatment was also associated with a significant decrease in total and low density lipoprotein (LDL) cholesterol (p < 0.05) with no effect on high density lipoprotein (HDL) cholesterol or triglycerides. Ribose-cysteine treatment significantly reduced atheroslcerosis lesion area in both the aortic sinus and brachiocephalic branch (p < 0.05) of treated animals.

    Conclusions: Ribose-cysteine exerts an antioxidant effect by increasing GSH-based antioxidant status and lowering oxidised lipids. This combined with its LDL-lowering property, suggest that it might be an ideal supplementary intervention to increase protection against CVD.

  • scan_tcga tools for integrated epigenomic and transcriptomic analysis of tumor subgroups.
  • Aniruddha Chatterjee, Peter A Stockwell, Euan J Rodger, Matthew F Parry, and Michael R Eccles., Epigenomics 2016 p. epi-2016-0063.
  • Published:14 September 2016
  • AIM:The Cancer Genome Atlas contains multiple levels of genomic data (mutation, gene expression, DNA methylation, copy number variation) for 33 cancer types for almost 11,000 patients. However, a dearth of appropriate software tools makes it difficult for bench scientists to use these data effectively.

    METHODS:Here, we present a suite of flexible, fast and command line-based scripts that will allow retrieval and analysis of DNA methylation (tool: scan_tcga_methylation.awk), mRNA (tool: scan_tcga_mRNA.awk) and miRNA expression (tool: scan_tcga_miRNAs.awk) from cancer genome atlas network level 3 data.

    RESULTS:We demonstrate the utility of these tools by analyzing DNA methylation and mRNA expression signatures of 60 frequently deregulated cancer genes and also of 30 miRNAs in primary (n = 102) and metastatic melanoma patients (n = 367).

    CONCLUSION:Our analysis illustrates the validity of the scan_tcga tools and reveals the epigenomic signatures and importance of identifying smaller patient subgroups with distinct molecular profiles.