Faculty of Biological Sciences

Dr Kenneth McDowall

BSc, Edinburgh; PhD 1991, Glasgow.
Pro-Dean for Student Education, Senior Lecturer
School of Molecular and Cellular Biology

Background: Joined the academic staff of the University of Leeds in 1996 after postdoctoral at Stanford University, California.

Contact:  Garstang 8.52d, +44(0) 113 34 33109/33089, email address for  

You can read more about Dr McDowall's interests here:
www.astbury.leeds.ac.uk/People/staffpage.php?StaffID=KMcD

(KJM figure 1)

Research Interests

Macromolecular and genetic interactions that regulated gene expression.

Research interests: The principal focus of the laboratory is the functional analysis of key events controlling gene expression. Of particular interest are the mechanisms that regulate and determine the nature of RNA decay and processing in E. coli and antibiotic production in S. coelicolor. Synthetic oligonucleotide chemistry, mass spectrometry, electron microscopy and surface plasmon resonance are all used in conjunction with a wide variety of biochemical techniques, bacterial genetics and bioinformatics. 

Current Projects

Structural and functional analysis of RNA decay

The cellular level of RNA transcripts is a major determinant of gene expression in all living organisms, and is controlled as much by the process of RNA decay as the initiation of transcription. Although it is well established that RNA decay is a highly regulated process and that the stability of transcripts in E. coli can extend over two orders of magnitude, an understanding of the molecular mechanisms that underlie this aspect of gene expression is only now beginning to emerge. Much of our work in this area focuses on RNaseE, an E. coli endoribonuclease that initiates the decay of many if not most transcripts, is required for rRNA processing, and is evolutionarily conserved. The functions of RNaseE also extend far beyond that of a simple ribonuclease: it serves as a platform upon which other enzymes involved in E. coli RNA decay assembly to form a complex called the RNA degradosome. One of the major challenges is to determine the relationship between the functions of the individual components and their close physical association. To provide a framework for understanding ongoing genetic and biochemical analyses of the degradosome, we are currently analysing the structural relationship of components using transmission electron microscopy, analytical centrifugation, and cross-linking studies.

We are also gaining new insight into the enzymology of the catalytic domain of RNaseE (and sequence homologues), the regulation of cleavage by ancillary domains of RNaseE, and the contribution of RNaseE activities to degradosome-function by studying the decay of modified RNA substrates that are synthesised using a combination of phosphoramidite chemistry and recombination techniques. The enzymology of the RNaseE family is being studied as part of a fully funded project that is being undertaken with Dr. Jane Grasby (University of Sheffiled). We are also investigating the extent to which control events mediated by RNaseE-like activities are evolutionarily conserved. This work is being done as part of a collaboration with Drs Alexander von Gabain and Vladimir Kaberdin Vienna Biocenter, Austria.

Global analysis of E. coli gene expression

In collaboration with Prof. Peter Stockley, we are using the latest gene array technology to study the impact on global gene expression of mutations that through structural and functional studies are known to alter co-operativity, sequence recognition, multimerisation or small molecule binding of transcription factors. We are also determining a stability profile for the E. coli transcriptome, which in turn should provide an unprecedented opportunity to examine the integrated regulation of transcription and mRNA decay and determine the influence of individual RNA-decay factors on the stability of each member of the E. coli mRNA pool. The above project, which is funded, involves continued collaboration with groups based outside Leeds including Prof. Martin Buck, Imperial College.

Transcriptional regulation during stress and development

Streptomycetes are mycelial prokaryotes that respond to environmental stress by producing survival spores via a complex development pathway and by synthesising complex macromolecular compounds many of which have been found to have antimicrobial activity. Indeed this group of microbes makes two-thirds of all the natural antibiotics that are used clinically as well as several drugs that are used in the treatment of cancer and parasitic infections. In collaboration with Prof. Simon Baumberg, we are investigating the mechanisms that regulate antibiotic production by Streptomyces coelicolor and its morphological development in response to phosphate starvation, which is the major nutrient stress faced by soil dwelling organisms. At present, we are using the power of genetics to identify key regulatory components; however, with the sequencing of the Streptomyces coelicolor genome nearing completion it should be possible to rapidly purify individual components and begin to piece together the molecular interactions (at both the structural and functional level) that underlie this rudimentary biological response.

Each research interest is currently supported by external funding from the BBSRC and the Royal Society.

 

Faculty Research and Innovation



Studentship information

Undergraduate project topics:

  • Cloning and expression of genes, and purification of protein complexes

Postgraduate studentship areas:

  • The analysis of gene regulatory networks (e.g. mRNA decay and processing, and antibiotic production) and protein:nucleic acid interactions using transcriptome and proteome analyses in hand with genetics and biochemistry

See also:

Modules managed

BIOL5382M - Extended Research Project

Modules taught

BIOC1301 - Introductory Integrated Biochemistry: the Molecules and Processes of Life
BIOC3160 - Laboratory/Literature/Computing Research Project
BIOC3231/32/BIOL3211/MICR3212 a - ATU - Life of an RNA
BIOC3231/32/BIOL3211/MICR3212 d - ATU - Human-microbe interactions
BIOL2110 - The Power of Bacterial Genomics
BIOL2111/BIOC2301 - Integrated Biochemistry/Genetic Engineering
BIOL2301/03/MICR2320 - Skills for Biol Sci and Microbiology
BIOL3398 - Research Tools and Applications
BIOL3399 - Extended Research Project Preparation
BIOL5372M - Advanced Biomolecular Technologies
BIOL5394M - Specialised Research Topics and Skills
BIOW5901X - Foundation module
BIOW5902X - Medicinal Chemistry and Drug Design
BLGY1232 - Introduction to Genetics
BLGY3110 - Applied Genetics
BMSC2120 - Scientific Skills
MICR3110 - Medical Microbiology Research Project

Committees

Chair of Faculty Taught Student Education Committee (Pro-Dean for Student Education)
Member of Graduate School Committee
Member of Masters Taught Student Education Committee (Pro-Dean for Taught Student Education (ex officio))
Member of Taught Student Recruitment Group
Member of Undergraduate School Taught Student Education Committee (Pro-Dean for Student Education (ex officio))

Centre memberships:

Group Leader Dr Kenneth McDowall  (Pro-Dean for Student Education, Senior Lecturer)

Macromolecular and genetic interactions that regulated gene expression. 

Postgraduates

Ayat Al-Tarawni (Primary supervisor) 60% FTE
Fayez Alsulaimani (Primary supervisor) 90% FTE
Jaskiran Sabharwal (Primary supervisor) 80% FTE
Asma Akter (Co-supervisor) 30% FTE
Zeyad Alzeyadi (Co-supervisor) 10% FTE
Elham Elkrewi (Co-supervisor) 10% FTE
Sophie Hazelden (Co-supervisor) 50% FTE
Victoria Lee (Co-supervisor) 10% FTE
Connor Macey (Co-supervisor) 50% FTE
Katie McDermott (Co-supervisor) 40% FTE
Jennifer Mitchell (Co-supervisor) 50% FTE
Divya Thankachan (Co-supervisor) 10% FTE

Romero DA, Hasan A, Lin Y, Kime L, Ruiz-Larrabeiti O, Urem M, Bucca G, Mamanova L, Laing EE, van Wezel GP, Smith CP, Kaberdin VR, Mcdowall KJ A comparison of key aspects of gene regulation in Streptomyces coelicolor and Escherichia coli using nucleotide-resolution transcription maps produced in parallel by global and differential RNA sequencing Molecular Microbiology 94 963-987, 2014
DOI:10.1111/mmi.12810
View abstract

Clarke JE, Kime L, Romero Alvarez D, McDowall KJ Direct entry by RNase E is a major pathway for the degradation and processing of RNA in Escherichia coli Nucleic Acids Research 42 11733-11751, 2014
DOI:10.1093/nar/gku808
View abstract

Kime L, Clarke JE, Romero Alvarez D, Grasby JA, McDowall KJ Adjacent single-stranded regions mediate processing of tRNA precursors by RNase E direct entry. Nucleic Acids Research 42 4577-4589, 2014
DOI:10.1093/nar/gkt1403
View abstract

Watson MR, Lin YF, Hollwey E, Dodds RE, Meyer P, McDowall KJ An improved binary vector and escherichia coli strain for agrobacterium tumefaciens-mediated plant transformation G3: Genes, Genomes, Genetics 6 2195-2201, 2016
DOI:10.1534/g3.116.029405
View abstract

Kim SH, Traag BA, Hasan AH, McDowall KJ, Kim B-G, van Wezel GP Transcriptional analysis of the cell division-related ssg genes in Streptomyces coelicolor reveals direct control of ssgR by AtrA Antonie van Leeuwenhoek, International Journal of General and Molecular Microbiology 108 201-213, 2015
DOI:10.1007/s10482-015-0479-2
View abstract

Li X, Yu T, He Q, Mcdowall KJ, Jiang B, Jiang Z, Wu L, Li G, Li Q, Wang S, Shi Y, Wang L, Hong B Binding of a biosynthetic intermediate to AtrA modulates the production of lidamycin by Streptomyces globisporus Molecular Microbiology -, 2015
DOI:10.1111/mmi.13004
View abstract

Kime L, Vincent HA, Gendoo DMA, Jourdan SS, Fishwick CWG, Callaghan AJ, McDowall KJ The first small-molecule inhibitors of members of the ribonuclease E family Scientific Reports 5 -, 2015
DOI:10.1038/srep08028
View abstract

Kime L, Vincent HA, Gendoo DM, Jourdan SS, Fishwick CW, Callaghan AJ, McDowall KJ Erratum: The First Small-Molecule Inhibitors of Members of the Ribonuclease E Family. Scientific reports 5 9781-, 2015
DOI:10.1038/srep09781

Lin YF, Romero Alvarez D, Guan S, Mamanova L, McDowall KJ A combination of improved differential and global RNA-seq reveals pervasive transcription initiation and events in all stages of the life-cycle of functional RNAs in Propionibacterium acnes, a major contributor to wide-spread human disease BMC Genomics 14 -, 2013
DOI:10.1186/1471-2164-14-620
View abstract

van Wezel GP, McDowall KJ The regulation of the secondary metabolism of Streptomyces: new links and experimental advances NAT PROD REP 28 1311-1333, 2011
DOI:10.1039/c1np00003a

Sargeant HR, McDowall KJ, Miller HM, Shaw MA Dietary zinc oxide affects the expression of genes associated with inflammation: Transcriptome analysis in piglets challenged with ETEC K88 VET IMMUNOL IMMUNOP 137 120-129, 2010
DOI:10.1016/j.vetimm.2010.05.001

Kime L, Jourdan SS, Stead JA, Hidalgo-Sastre A, McDowall KJ Rapid cleavage of RNA by RNase E in the absence of 5' monophosphate stimulation MOL MICROBIOL 76 590-604, 2010
DOI:10.1111/j.1365-2958.2009.06935.x

Nothaft H, Rigali S, Boomsma B, Swiatek M, McDowall KJ, van Wezel GP, Titgemeyer F The permease gene nagE2 is the key to N-acetylglucosamine sensing and utilization in Streptomyces coelicolor and is subject to multi-level control MOL MICROBIOL 75 1133-1144, 2010
DOI:10.1111/j.1365-2958.2009.07020.x

Nothaft H, Rigali S, Boomsma B, Swiatek M, McDowall KJ, van Wezel GP, Titgemeyer F The permease gene nagE2 is the key to N-acetylglucosamine sensing and utilization in Streptomyces coelicolor and is subject to multi-level control. Mol Microbiol -, 2010
DOI:10.1111/j.1365-2958.2010.07020.x
View abstract

Jourdan SS, Kime L, McDowall KJ The sequence of sites recognised by a member of the RNase E/G family can control the maximal rate of cleavage, while a 5 '-monophosphorylated end appears to function cooperatively in mediating RNA binding BIOCHEM BIOPH RES CO 391 879-883, 2010
DOI:10.1016/j.bbrc.2009.11.156

Carpousis AJ, Luisi BF, McDowall KJ Chapter 3 Endonucleolytic Initiation of mRNA Decay in Escherichia coli Progress in Nucleic Acid Research and Molecular Biology 84 91-135, 2009
DOI:10.1016/S0079-6603(08)00803-9
View abstract

McDowall KJ Chemistry, measurement and modulation of RNA stability In Wiley Encyclopedia of Chemical Biology , 2009
View abstract

Carpousis AJ, Luisi BF, McDowall KJ Endonucleolytic Initiation of mRNA Decay in Escherichia coli In Progress in Molecular Biology and Translational Science , 2009
DOI:10.1016/S0079-6603(08)00803-9
View abstract

Kime L, Jourdan SS, McDowall KJ Chapter 12 Identifying and Characterizing Substrates of the RNase E/G Family of Enzymes Methods in Enzymology 447 215-241, 2008
DOI:10.1016/S0076-6879(08)02212-X
View abstract

Resch A, Afonyushkin T, Lombo TB, McDowall KJ, Blasi U, Kaberdin VR Translational activation by the noncoding RNA DsrA involves alternative RNase III processing in the rpoS 5 '-leader RNA 14 454-459, 2008
DOI:10.1261/rna.603108

Kime L, Jourdan SS, McDowall KJ Identifying and Characterizing Substrates of the RNase E/G Family of Enzymes In Methods in Enzymology , 2008
DOI:10.1016/S0076-6879(08)02212-X
View abstract

Jourdan SS, McDowall KJ Sensing of 5 ' monophosphate by Escherichia coli RNase G can significantly enhance association with RNA and stimulate the decay of functional mRNA transcripts in vivo MOL MICROBIOL 67 102-115, 2008
DOI:10.1111/j.1365-2958.2007.06028.x

Hong B, Phornphisutthimas S, Tilley E, Baumberg S, McDowall KJ Streptomycin production by Streptomyces griseus can be modulated by a mechanism not associated with change in the adpA component of the A-factor cascade. Biotechnol Lett 29 57-64, 2007
DOI:10.1007/s10529-006-9216-2
View abstract

Stead JA, McDowall KJ Two-dimensional gel electrophoresis for identifying proteins that bind DNA or RNA NAT PROTOC 2 1839-1848, 2007
DOI:10.1038/nprot.2007.248

Stead JA, Keen JN, McDowall KJ The identification of nucleic acid-interacting proteins using a simple proteomics-based approach that directly incorporates the electrophoretic mobility shift assay. Mol Cell Proteomics 5 1697-1702, 2006
DOI:10.1074/mcp.T600027-MCP200
View abstract

Marincs F, Manfield IW, Stead JA, McDowall KJ, Stockley PG Transcript analysis reveals an extended regulon and the importance of protein-protein co-operativity for the Escherichia coli methionine repressor. Biochem J 396 227-234, 2006
DOI:10.1042/BJ20060021
View abstract

Callaghan AJ, Marcaida MJ, Stead JA, McDowall KJ, Scott WG, Luisi BF Structure of Escherichia coli RNase E catalytic domain and implications for RNA turnover. Nature 437 1187-1191, 2005
DOI:10.1038/nature04084
View abstract

Taib M, Pinney JW, Westhead DR, McDowall KJ, Adams DJ Differential expression and extent of fungal/plant and fungal/bacterial chitinases of Aspergillus fumigatus ARCH MICROBIOL 184 78-81, 2005
DOI:10.1007/s00203-005-0028-x

Uguru GC, Stephens KE, Stead JA, Towle JE, Baumberg S, McDowall KJ Transcriptional activation of the pathway-specific regulator of the actinorhodin biosynthetic genes in Streptomyces coelicolor. Mol Microbiol 58 131-150, 2005
DOI:10.1111/j.1365-2958.2005.04817.x
View abstract

Callaghan AJ, Redko Y, Murphy LM, Grossmann JG, Yates D, Garman E, Ilag LL, Robinson CV, Symmons MF, McDowall KJ, Luisi BF "Zn-Link": A metal-sharing interface that organizes the quaternary structure and catalytic site of the endoribonuclease, RNase E Biochemistry 44 4667-4675, 2005
DOI:10.1021/bi0478244
View abstract

Marincs F, McDowall KJ, Stockley PG A combined in vitro transposition-in vivo recombination mutagenesis method to knock out genes in Escherichia coli American Biotechnology Laboratory 22 8-10, 2004

Callaghan AJ, Grossmann JG, Redko Y, Ilag LL, Moncrieffe MC, Symmons MF, Robinson CV, Luisi BF, McDowall KJ Quaternary structure and catalytic activity of the Escherichia coli ribonuclease E amino-terminal catalytic domain Biochemistry 42 13848-13855, 2003
DOI:10.1021/bi0351099

Kaberdin VR, McDowall KJ Expanding the use of zymography by the chemical linkage of small, defined substrates to the gel matrix GENOME RES 13 1961-1965, 2003
DOI:10.1101/gr.1277303

Redko Y, Tock M, Adams CJ, Kaberdin VR, Grasby JA, McDowall KJ Determination of the Catalytic Parameters of the N-terminal Half of Escherichia coli Ribonuclease E and the Identification of Critical Functional Groups in RNA Substrates Journal of Biological Chemistry 278 44001-44008, 2003
DOI:10.1074/jbc.M306760200

Harding M, Hodgson R, Majid T, McDowall KJ, Nelson A A stereodivergent, two-directional synthesis of stereoisomeric C-linked disaccharide mimetics. Org Biomol Chem 1 338-349, 2003
View abstract

Walsh AP, Tock MR, Mallen MH, Kaberdin VR, von Gabain A, McDowall KJ Cleavage of poly(A) tails on the 3 '-end of RNA by ribonuclease E of Escherichia coli NUCLEIC ACIDS RES 29 1864-1871, 2001

Kaberdin VR, Walsh AP, Jakobsen T, McDowall KJ, von Gabain A Enhanced cleavage of RNA mediated by an interaction between substrates and the arginine-rich domain of E-coli ribonuclease E Journal of Molecular Biology 301 257-264, 2000
View abstract

Tock M, Walsh AP, Carroll G, McDowall KJ The CafA protein required for the 5 '-maturation of 16 S rRNA is a 5'-end-dependent ribonuclease that has context-dependent broad sequence specificity Journal of Biological Chemistry 275: (12) 8726-8732, 2000
View abstract

McDowall KJ Phosphate control of oxytetracycline production by Streptomyces rimosus Is at the level of transcription from promoters overlapped by tandem repeats similar to those of the DNA-binding sites of the OmpR family Journal of Bacteriology 181 3025-3032, 1999

Kaberdin VR, Miczak A, Jakobsen JS, Lin-Chao S, McDowall KJ, von Gabain A The endoribonucleolytic N-terminal half of E. coli RNaseE is evolutionarily conserved in Synechocystis sp, other bacteria and a plastid, but not the sequence of the C-terminal half which is sufficient for degradosome assembly Proceedings of the National Academy of Sciences of the United States of America 95 11637-11642, 1998
View abstract

McDowall KJ RNase E: Still a wonderfully mysterious enzyme Molecular Microbiology 23 1099-1106, 1997

McDowall KJ, Cohen SN The N-terminal domain of the rne gene product has RNase E activity and is nonoverlapping with the arginine-rich RNA-binding site Journal of Molecular Biology 255 349-355, 1996
View abstract

McDowall KJ Site-specific RNase E cleavage of oligonucleotides and inhibition by stem-loops. Nature 374 287-290., 1995

McDowall KJ A+U content rather than a particular nucleotide order determines the specificity of RNase E cleavage. J Biol Chem 269 10790-10796., 1994

McDowall KJ The ams-1 and rne-3071 temperature-sensitive mutations in the ams gene are in close proximity to each other and cause substitutions within a domain that resembles a product of the Escherichia coli mre locus. J. Bacteriol 175 4245-9., 1993

Kennedy L, McDowall KJ, Sutherland IW Alginases from Azotobacter species Journal of General Microbiology 138 2465-2471, 1992
View abstract

McDowall KJ, Doyle D, Butler MJ, Binnie C, Warren M, Hunter IS Molecular genetics of oxytetracycline production by Streptomyces rimosus In Genetics and product formation in Streptomyces , 1991

Doyle D, McDowall KJ, Butler MJ, Hunter IS Characterization of an oxytetracycline resistance gene, otrA, of Streptomyces rimosus Molecular Microbiology 5 2923-2933, 1991
DOI:10.1111/j.1365-2958.1991.tb01852.x
View abstract