Professor Steve Busby FRS

School of Biosciences
Professor of Biochemistry

Contact details

Telephone: +44 (0)121 414 5439
Email: s.j.w.busby@bham.ac.uk

Address: School of Biosciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
UK

Research in Steve Busby’s lab is concerned with understanding the molecular mechanisms that control gene expression in bacteria, with particular attention to studying the regulation of transcription initiation in Escherichia coli. Much of the recent work has focussed on the expression of virulence determinants in pathogenic strains.

Staff details
Media information
Policy information

Qualifications

BA 1972 University of Cambridge, Natural Sciences
DPhil 1975 University of Oxford

Biography

Postdocs 1975-1979 Institut Pasteur, Paris & NIH, Bethesda
1979-1983 Staff Scientist at Institut Pasteur, Paris
1983 Lecturer at the University of Birmingham
1988 Senior Lecturer
1990-1995 Royal Society EPA Fund Research Fellow & Reader in Biochemistry
1995-present Professor of Biochemistry
2005 FRS
2006 Fellow of the American Academy of Microbiology
2016 Fellow of the Royal Society of Biology

Teaching

Steve teaches on undergraduate courses at all levels. His biggest contributions are to a second year course on bacterial genes and genomes, and a third year course on bacterial gene regulation. He is currently the Coordinator for the School’s Taught Masters and MRes Programmes.

Postgraduate supervision

For a list of possible PhD projects offered by Prof Busby www.findaphd.com/search/customlink.asp?inst=birm-Biol&supersurname=Busby

Former PhDs from the Busbylab include: Vas Ponnambalam (1984-1987), Bernard Chan (1985-1988), Sheela Jayaraman (1985-1988), Tim Peakman (1985-1988), Kevin Gaston (1986-1989), Andrew Bell (1987-1990), Matt Downham (1989-1992), Roy Williams (1989-1992), Jackie Williams (1990-1993), Kerry Tyson (1990-1993), David West (1991-1994), Virgil Rhodius (1992-1995), Jennifer Keen (1993-1996), Helen Wing (1993-1996), Steve Williams (1994-1997), Hui-chung Wu (1994-1997), Emma Law (1995-1999), David Lee (1996-2000), Tom Burr (1996-2000), Paolo Landini (1996-2000),Tamara Belyaeva (1996-2001), John Tebbutt (1997-2000), Andrew Sanderson (1998-2001), Joseph Wade (1998-2001), Mohamed Samir el Robh (1999-2002), Lars Westblade (1999-2002), David Grainger (2000-2003), Nora Miroslavova (2001-2004), Christina Kahramanoglou (2001-2004), Jennie Mitchell (pt time 2002-2009), Shivanthi Rodrigo (2004-2007), Sarah Piper (2004-2007), Meng Xu (2004-2008), Kerry Hollands (2005-2008), David Chismon (2006-2009), Mohamed Islam (2007-2011), Jack Bryant (2008-2012), Patcharawarin Ruanto (2009-2013), Laura Sellars (2009-2013), Ghadah alSharif (2010-2015), Bandar Sendy (2012-2017), Muhamad Yasir (2012-2017)

Research

Research Theme within School of Biosciences: Microbiology & Infection

Transcriptional regulation in bacteria

Steve Busby’s work concerns the mechanisms by which the expression of different genes is regulated in bacteria. Working with Escherichia coli K-12, over the past 35 years, the lab has elucidated some of the basic rules of promoter recognition by RNA polymerase and some of the fundamental mechanisms by which transcription activators function (see reviews listed below).

The work with RNA polymerase has focused on the roles of the alpha and sigma subunits, whilst the work on transcription activation has developed from studies of the cyclic AMP receptor protein (known as CRP or CAP), which have established a paradigm for understanding transcription activation in bacteria. Early work with CRP, and with the related activator, FNR, was concerned with simple promoters, such as the E. coli lac or gal operon promoters, where one molecule of activator is sufficient for full induction. Later on, the lab turned its attention to more complicated promoters that are regulated by many different factors. Because bacterial gene expression is exquisitely sensitive to the environment, the majority of promoters are complex, and the lab has focused on cases where one molecule of activator is insufficient for full induction. The work has identified novel mechanisms for co-activation of promoters by multiple activators.

Current active projects concern:

The relation between the activity of bacterial promoters and their location within the bacterial folded chromosome and epigenetic effects on bacterial gene expression
Understanding the molecular mechanisms whereby activation at CRP- and FNR-dependent promoters is coupled to other activators. These promoters function as integration devices that coordinate transcriptional responses to different environmental signals.
Exploitation of bacterial regulatory elements for biotechnology applications. We have produced a new set of vectors for controlled overexpression of foreign proteins, targeting them to the bacterial periplasm
Understanding promoters that regulate the expression of some of the major virulence determinants of pathogenic E. coli and finding ways to disrupt their activity.

Collaborators

David Lee (Birmingham City University) & Matej Butala (Ljubljana University), DNA sampling;
Achilles Kapinidis (Oxford University), Single-molecule fluorescence measurements;
Rob Neeley (University of Birmingham), Fluorescent methyl transferase substrates;
Alan Wolfe (Loyola University, Chicago), Manuel Canovas (University of Murcia) &V Nagaraja (IISc Bangalore), Acetylation of bacterial proteins;
Stephanie Schuller & Muhamad Yasir (Quadram Institute, Norwich)
Julio Collado-Vides (UNAM Cuernavaca), E. coli databases

Other activities

Vice Chair then Chair of the Biochemical Society (2011-2016)

Head of University of Birmingham School of Biosciences (2012-2016)

Member of BBSRC Committee E (Fellowships)

During the past 2 years, Steve gave invited lectures at: Solihull 6^th Form College (Biology Dept); University of Manchester Leaders in Science Lecture (Faculty of Life Sciences); University of Warwick (Division of Microbiology & Infection); University of Oxford (Synthetic Circuit Design MSc);Oundle School 6^th Form (Evening Lecture Series); University of Birmingham (Biosciences Evening Lecture series); Concord College, Shrewsbury (Readers and Writers Festival); West Midlands Guild of Graduates Evening Lecture; Rutherford Appleton Laboratory (Harwell); NCBS Molecular Biology (Bangalore); ASE Annual Meeting (Birmingham); University of Salford (Health Forum); University of Marburg (Microbiology); Loyola University Medical School (Chicago); UAM Cuernavaca (Bioinformatics); Denbigh High School (Milton Keynes); NUS Mechanobiology Institute (Singapore)

During the past 24 months, Steve spoke at the following international meetings: Synthetic Biology in Action Course (EMBO Lab Heidelberg); 13^th FASEB meeting on Bacterial Transcription (Vermont, USA); 77^th Harden Conference on 2-component signaling in bacteria (Chesford Grange, Warwickshire); M4 Midland Microbiology Meeting (Nottingham); 7^th Sunny Forum (Sun-Yat Sen University, Guangzhou); Indian Institute of Science-MCB75 Meeting (Bangalore); ASM Annual Meeting Microbe 2016 (Boston, USA); Microbiology Society Annual Meeting Marjory Stephenson Lecture (Edinburgh); BIOTEC2017 Plenary Lecture (Murcia, Spain); 14^th FASEB meeting on Bacterial Transcription (Vermont, USA)

Publications

Key reviews

Busby, S J W & Radda, G K (1976) Regulation of the glycogen phosphorylase system - from physical measurements to biological speculations. Current Topics in Cell Regulation 10 89-160
de Crombrugghe, B, Busby, S & Buc, H (1984) Cyclic AMP receptor protein: role in transcription activation. Science 224 831-838
Busby, S & Buc, H (1987) Positive regulation of gene expression by cyclic AMP and its receptor protein in E. coli. Microbiological Sciences 4 371-375
Kolb, A, Busby, S, Buc, H, Garges, S & Adhya, S (1993) Transcriptional regulation by cyclic AMP and its receptor protein. Annu. Rev. Biochem. 62 749-795
Busby, S & Ebright, R (1994) Promoter structure, promoter recognition and transcription activation in prokaryotes. Cell 79 743-746
Ebright, R & Busby, S (1995) Escherichia coli RNA polymerase alpha subunit: structure and function. Current Opinion in Genetics and Development 5 197-200
Busby, S & Kolb, A (1996) The CAP Modulon. In Regulation of Gene Expression in E. coli (Lin, E & Lynch, S, eds) chapter 12, pp 255-279, R.G. Landes, New York
Busby, S & Ebright, R (1997) Transcription activation at Class II CAP-dependent promoters. Molecular Microbiology 23 853-859
Busby, S & Ebright, R (1999) Transcription activation by catabolite activator protein (CAP). J. Mol. Biol. 293 199-213.
Lloyd, G, Landini, P, & Busby, S (2001) Activation and repression of transcription initiation in bacteria. Essays in Biochemistry, vol 37, chapter 2, pp 17-32.
Browning, D & Busby, S (2004) The regulation of bacterial transcription initiation. Nature Reviews Microbiology 257-65
Barnard, A, Wolfe, A & Busby, S (2004) Regulation at complex bacterial promoters: how bacteria use different promoter organisations to produce different regulatory outcomes. Current Opinion in Microbiology 7 102-108
Busby, S & Savery, N (2007) Transcription activation at bacterial promoters. Online Encyclopaedia of Life Science, http://www.els.net/, John Wiley & Sons, Ltd, Chichester
Wade, JT, Struhl, K, Busby, SJW & Grainger, DC (2007) Genomic analysis of protein-DNA interactions in bacteria: insights into transcription and chromosome organization. Molecular Microbiology 65 21-26
Grainger, D & Busby, S (2008) Global regulators of E coli transcription: mechanisms of action and methods for study. Advances in Applied Microbiology 65 93-113
Butala, M, Zgur-Bertok, D & Busby, S (2009) The bacterial LexA transcriptional repressor. Cellular and Molecular Life Sciences 66 82-93
Browning, D, Savery, N, Kolb, A & Busby, S (2009) Assays for transcription factor activity. Methods in Molecular Biology: DNA-Protein interactions 3^rd Edition (Benoit LeBlanc & Tom Moss, eds.) Volume 543, Chapter 23, pp 369-387, Springer Science
Grainger, D, Lee, D & Busby, S (2009) Direct methods for studying transcription regulatory proteins and RNA polymerase in bacteria. Current Opinion in Microbiology 12 531-535
Browning, D, Grainger, D & Busby S (2010) Effects of nucleoid-associated proteins on bacterial chromosome structure and gene expression. Current Opinion in Microbiology 13 773-780
Lee, DJ, Minchin, SD & Busby SJW (2012) Activating transcription in bacteria. Annu. Rev. Microbiol. 66 125-152
Visweswariah, SS & Busby SJW (2015) Evolution of bacterial transcription factors: how proteins take on new tasks, but do not always stop doing the old ones. Trends in Microbiology doi: 10.1016/j.tim.2015.04.009.
Browning, D & Busby, S (2016) Local and global regulation of transcription initiation in bacteria. Nature Reviews Microbiology 14 638-650
Busby SJ (2019) Transcription activation in bacteria: ancient and modern. Microbiology 163 386-395

Selected Research Publications since 2007

(for full list, search Busby SJ on Pubmed, or use Google Scholar)

Grainger, D, Aiba, H, Hurd, D, Browning, D & Busby, S (2007) Transcription factor distribution in E coli: studies with FNR protein. Nucl. Acids Res. 35 269-278
Mitchell, J, Oshima, T, Piper, S, Webster, C, Westblade, L, Karimova, G, Ladant, D, Kolb, A, Hobman, J, Busby, S & Lee D (2007) The Escherichia coli Regulator of Sigma 70 protein, Rsd, can up-regulate some stress-dependent promoters by sequestering Sigma 70. J. Bacteriol. 189 3489-3495
Kedzierska, B, Szambowska, A, Herman-Antosiewicz, A, Lee, D. Busby, S. Wegrzyn, G & Thomas, M (2007) The C-terminal domain of the Escherichia coli RNA polymerase a subunit plays a role in the CI-dependent activation of the bacteriophage l p_M promoter. Nucl. Acids Res 35 2311-2320
Hollands, K, Busby, S & Lloyd, G (2007) New targets for the cyclic AMP receptor protein in the E. coli K-12 genome. FEMS Letters 274 89-94
Lee, D, Busby, S, Westblade, L & Chait B (2008) Affinity isolation and I-DIRT mass spectrometric analysis of the Escherichia coli O157:H7 Sakai RNA polymerase complex. J. Bacteriol 190 1284-1289
Samarasinghe, S, El-Robh, M, Grainger, D, Zhang, W, Soultanas, P & Busby, S (2008) Autoregulation of the Escherichia coli melR promoter: repression involves four molecules of MelR. Nucl. Acids Res. 36 2667-2676
Grainger, D, Goldberg, M, Lee, D & Busby, S (2008) Selective repression by Fis and H-NS at the Escherichia coli dps promoter. Molecular Microbiology 68 1366-1377
Shimada, T, Ishihama, A, Busby, S & Grainger D (2008) The Escherichia coli RutR transcription factor binds at targets within genes as well as intergenic regions. Nucl Acids Res. 36 3950-3955
Browning, D, Cole, J & Busby, S (2008) Regulation by nucleoid-associated proteins at the Escherichia coli niroperon promoter. J. Bacteriol 190 7258-7267
Lloyd, G, Hollands, K, Godfrey R & Busby S (2008) Transcription initiation in the E coli K-12 malI-malX intergenic region and the role of the cyclic AMP receptor protein. FEMS Letters 258 250-257
Butala, M, Busby, S & Lee, D (2009) DNA sampling: a method for probing protein binding at specific loci on bacterial chromosomes. Nucl Acids Res doi:10.1093/nar/gkp043
Xu, M, Busby, S & Browning, D (2009) Activation and repression at the Escherichia coli ynfEFGHI operon promoter. J Bacteriol 191 3172-3176
Squire, D, Xu, M, Cole, J, Busby, S & Browning, D (2009) Competition between NarL-dependent activation and Fis-dependent repression controls expression from the Escherichia coli yeaR and ogt promoters. Biochem J 420249-257
Piper, S, Mitchell, J, Lee, D & Busby, S(2009) A global view of Escherichia coli Rsd protein and its interactions. Molecular BioSystems 5 1943-1947
Lee, D, Bingle, L, Heurlier, K, Pallen, M, Penn, C, Busby, S & Hobman, J (2009) Gene doctoring: a method for recombineering in laboratory and pathogenic Escherichia coli strains. BMC Microbiology 9 252
Hollands, K, Lee, D, Lloyd, G & Busby, S (2010) Activation of sigma 28-dependent transcription in Escherichia coli by the cyclic AMP receptor protein requires an unusual promoter organisation. Molecular Microbiology 75 1098-1111
Lloyd, G, Godfrey R & Busby S (2010) Targets for the MalI repressor at the divergent Escherichia coli K-12 malX-malI promoters. FEMS Letters 305 28-34
Sánchez-Romero, M-A, Busby, S, Dyer, N, Ott, S, Millard, A & Grainger, D (2010) Dynamic distribution of SeqA protein across the chromosome of Escherichia coli K-12. mBio 1 e00012-10.doi10.1128/mBio00012-10
Browning, D, Lee, D, Spiro, S & Busby, S (2010) Down-regulation of the Escherichia coli K-12 nrf promoter by binding of the NsrR nitric oxide sensing transcription repressor to an upstream site. J. Bacteriol 192 3824-3828
Chismon, D, Browning, D, Farrant, G & Busby, S (2010) Unusual organization, complexity and redundancy at the Escherichia coli hcp-hcr promoter. Biochem J 430 61-68
Islam, MS, Bingle, L, Pallen, M & Busby, S (2011) Organization of the LEE1 operon regulatory region of enterohaemorrhagic Escherichia coli O157:H7 and activation by GrlA. Molecular Microbiology 79 468-483
Yamamoto, K, Ishihama, A., Busby, S & Grainger, D (2011) The Escherichia coli K-12 MntR miniregulon includes dps, which encodes the major stationary phase DNA-binding protein. J. Bacteriol 193 1477-1480
Butala, M, Klose, D, Hodnik, V, Rems, A, Podlesek, Z, Klare, J, Anderluh, G, Busby, S, Steinhoff, H-J & Žgur‑Bertok, D (2011) Interconversion between bound and free conformations of LexA orchestrates the bacterial SOS response. Nucl Acids Res. 39 6546-6557
Islam, MS, Pallen, M & Busby, S (2011) A cryptic promoter in the LEE1 regulatory region of enterohaemorrhagic Escherichia coli: promoter specificity in AT-rich gene regulatory regions. Biochem J 436 681-686
Rossiter, A, Browning, D, Leyton, D, Johnson, M, Godfrey, R, Wardius, C, Desvaux, M, Cunningham, A, Ruiz-Perez, F, Nataro, J, Busby, S & Henderson, I (2011) Transcription of the plasmid-encoded toxin gene from enteroaggregative Escherichia coli is regulated by a novel co-activation mechanism involving CRP and Fis. Molecular Microbiology 81 179-191
Islam, MS, Shaw RK, Frankel G, Pallen, M & Busby, S (2012) Translation of a minigene in the 5’ leader sequence of the enterohemorrhagic Escherichia coli LEE1 transcription unit affects expression of the neighbouring downstream genes. Biochem J. 441 247-253
Sánchez-Romero MA, Lee D, Sánchez-Morán E & Busby SJ. (2012) Location and dynamics of an active promoter in Escherichia coli K-12. Biochem J. 441 481-486
Butala, M, Sonjak, S, Kamensek, S, Hodoscek, M, Browning, D, Zgur-Bertok, D & Busby, S (2012) Double locking of an Escherichia coli promoter by two repressors prevents premature colicin expression and cell lysis. Molecular Microbiology 86 129-139
Ricci, V, Busby, S & Piddock, L (2012) Regulation of RamA by RamR in Salmonella enterica Serovar Typhimurium: isolation of a RamR superrepressor. Antimicrob Agents Chemother 56 6037-6040
Lee, D & Busby, S (2012) Repression by cAMP receptor protein at a distance. mBio 3 e00289-12 doi 10 1128/mBio00289-12
Elrobh, M, Webster, C, Samarasinghe, S, Durose, D & Busby, S (2013) Two DNA sites for MelR in the same orientation are sufficient for optimal MelR-dependent repression at the Escherichia coli melR promoter. FEMS Letters 338 62-67
Lawler. A, Ricci, V, Busby, S & Piddock, L (2013) Genetic inactivation of acrAB or inhibition of efflux induces expression of ramA. J Antimicrob Chemother 68 1551-1557
Bingle, L, Constantinidou, C, Shaw, R, Islam, MS, Patel, M, Snyder, L, Lee, D, Penn, C, Busby, S & Pallen, M (2014) Microarray analysis of the Ler Regulon in Enteropathogenic and Enterohaemorrhagic Escherichia colistrains. PLOS One 9 e80160
Zhou, Y, Kolb, A, Busby, S & Wang YP (2014) Spacing requirements for Class I transcription activation in bacteria are set by promoter elements. Nucl Acids Res. 42 9209-9216
Bryant, J, Sellars, L, Busby, S & Lee D (2014) Chromosome position effects on gene expression in Escherichia coli. Nucl Acids Res. 42 11383-11392
Rossiter, A, Godfrey, R, Connolly, J, Busby, S, Henderson, I & Browning, D (2015) Expression of different bacterial cytotoxins is controlled by two global transcription factors, CRP and Fis, that co-operate in a shared-recruitment mechanism. Biochem J. 466 323-335
Alsharif, G, Ahmad, S, Islam, MS, Shah, R, Busby, S & Krachler AM (2015) Host attachment and fluid shear are integrated into a mechanical signal regulating virulence in Escherichia coli O157:H7. Proc. Natl. Acad. Sci. (USA) 112 5503-5508
Kamensek, S, Browning, DF, Podlesek, Z, Busby, SJ, Zgur-Bertok. D & Butala, M (2015) Silencing of DNase Colicin E8 gene expression by a complex nucleoprotein assembly ensures timely colicin induction. PLoS Genetics 11 e1005354
Sendy, B, Lee, DJ, Busby, SJ & Bryant JA (2016) RNA polymerase supply and flux through the lac operon in Escherichia coli. Phil Trans R Soc B 371 pii:20160080
Godfrey, RE, Lee, DJ, Busby, SJ & Browning, DF (2017) Regulation of nrf operon expression in pathogenic enteric bacteria: sequence divergence reveals new regulatory complexity Molecular Microbiology doi: 10.1111/mmi.13647
Garza de Leon, F, Sellars, LE, Stracy, M, Busby, SJ & Kapanidis, AN (2017) Tracking low-copy transcription factors in living bacteria: the case of the lac repressor. Biophysical Journal 112 1316-1327
Sellars, LE, Bryant JA, Sanchez-Romero, MA, Sanchez-Moran, E, Busby, SJ & Lee, DJ (2017) Development of a new fluorescent reporter-operator system; location of AraC-regulated genes in Escherichia coli K-12. BMC Microbiology DOI 10.1186/s12866-017-1079-2
Browning, DF, Richards, KL, Peswani, AR, Roobol, J, Busby, SJ & Robinson, C (2017) Escherichia coli ‘Tat Express’ strains super-secrete human growth hormone into the bacterial periplasm by the Tat pathway. Biotechnology & Bioengineering 114 2828-2836
Santos-Zavaleta, A, Sánchez-Pérez, M, Salgado, H, Velázquez-Ramírez, DA,Gama-Castro, S, Tierrafría, VH, Busby, SJW, Aquino, P, Fang, X, Palsson, BO, Galagan, JE & Collado-Vides, J (2018) A unified resource for transcriptional regulation in Escherichia coli K-12 incorporating high-throughput-generated binding data into RegulonDB version 10.0. BMC Biol. 2018 16 91. doi:10.1186/s12915-018-0555-y.
Yasir, M, Icke, C, Abdelwahab, R, Haycocks, JR, Godfrey, RE, Sazinas, P, Pallen, MJ, Henderson, IR, Busby, SJ & Browning, DF (2019) Organization and architecture of AggR-dependent promoters from enteroaggregative Escherichia coli. Mol Microbiol. 111 534-551
Ellis, SJ, Yasir, M, Browning, DF, Busby, SJ & Schuller, S (2019) Oxygen and contact with human intestinal epithelium independently stimulate virulence gene expression in enteroaggregative Escherichia coli. Cell Microbiol. Jan 23:e13012. doi: 10.1111/cmi.13012.
Browning, DF, Godfrey, RE, Richards, KL, Robinson, C & Busby, SJ (2019) Exploitation of the Escherichia coli lac-operon promoter for controlled recombinant protein production. Biochem Soc Trans. in the press.
Wand, NO, Smith, DA, Wilkinson, AA, Rushton, AE, Busby, SJW, Styles, IB & Neely, RK (2019) DNA barcodes for rapid, whole genome, single-molecule analysis. Nucl Acids Res. doi: 10.1093/nar/gkz212