Michelle Webb is determining the functional outcome of BRCA1 missense variants. This will help determine their pathogenicity.

Lecturer in Medical Genetics

School of Medicine
Stopford Building 3.614
Oxford Road
Manchester
M13 9PL

Tel: +44 (0)161 2751950
E-mail: michelle.webb@manchester.ac.uk

Dr Webb graduated from Portsmouth University in 1992 with a BSc in Molecular Biology. She a PhD in Portsmouth entitled “Biochemical Characterisation of the EcoR124I Type I DNA Modification Methylase” with Professor Geoff Kneale. In 1995 she moved to the University of Cambridge to join the laboratory of Professor Jean Thomas to study the interaction of HMG1 with DNA and Chromatin.

She was appointed to her first lectureship position in 1999 at the University of Sheffield where she began her research on the structural/functional characterisation of the breast cancer susceptibility proteins BRCA1 and BRCA2. In 2004 she was appointed as a Lecturer in Medical Genetics in Manchester where she now developing functional assays for BRCA1 missense mutations and point of care devices for disease, including breast cancer.

The eukaryotic elongation factor eEF1A1 interacts with SAMHD1.

Morrissey C, Schwefel D, Ennis-Adeniran V, Taylor IA, Crow YJ, Webb M.

Biochem J. 2015 Feb 15;466(1):69-76. doi: 10.1042/BJ20140203.

A guide for functional analysis of BRCA1 variants of uncertain significance.

Millot GA, Carvalho MA, Caputo SM, Vreeswijk MP, Brown MA, Webb M, Rouleau E, Neuhausen SL, Hansen Tv, Galli A, Brandão RD, Blok MJ, Velkova A, Couch FJ, Monteiro AN; ENIGMA Consortium Functional Assay Working Group.

Hum Mutat. 2012 Nov;33(11):1526-37. doi: 10.1002/humu.22150.

Developing functional assays for BRCA1 unclassified variants.

Webb M.

Methods Mol Biol. 2010;653:281-91. doi: 10.1007/978-1-60761-759-4_17.

Purification and characterisation of the breast cancer metastasis suppressor, BRMS1.

Smith J, Naseem R, Webb M.

Protein Expr Purif. 2009 Oct;67(2):70-5. doi: 10.1016/j.pep.2009.04.010.

Analysis of the DNA binding activity of BRCA1 and its modulation by the tumour suppressor p53.

Naseem R, Webb M.

PLoS One. 2008 Jun 11;3(6):e2336. doi: 10.1371/journal.pone.0002336.

Dr Webb has several projects in the field of breast cancer risk assessment detection and prognosis.

1. Functional assays

One of the difficulties associated with the development of a functional assay is that the BRCA1 gene encodes a large protein that performs a multiple cellular functions. No single assay will, therefore, be able to account for the functional effects of all missense variants. The different functions of BRCA1 are mediated by over fifty interactions that take place throughout the protein and while truncating mutations eliminate all binding sites downstream of them, and may also lead to nonsense mediated mRNA decay, pathogenic missense mutations are likely to affect only a single binding site. To assess the pathogenicity of these mutations we are developing a number of functional assays that are capable of determining their effects on the interactions of BRCA1.

2. Point of care devices that detect prognostic biomarkers of breast cancer enabling the development of personalised treatment regimes.

Biomarkers are not only useful for cancer diagnosis but also for determining aggressiveness and likelihood of responding to a given treatment. Examples of prognostic biomarkers in breast cancer include elevated expression of (i) estrogen receptor (ER) and/or progesterone receptor (PR), (ii) HER2/neu gene amplification, a marker indicating if breast cancer will likely respond to Herceptin treatment. Our aim is develop a low cost disposable point of care device that can simultaneously monitor a number of prognostic biomarkers for breast cancer and guide treatment decisions. We are using Organic Field Effect Transistors (OFETs) as signal transducers of biomarker binding. Such devices exhibit ultra-low detection limits and avoid the use of expensive fluorescent labeling protocols ensuring low cost production.

Foxon SP., Phillips T., Gill MR., Towrie M., Parker AW., Webb M., Thomas JA. (2007) A multifunctional light switch: DNA binding and cleavage properties of a heterobimetallic ruthenium-rhenium dipyridophenazine complex. Angew Chem Int Ed Engl. 46, 3686-3688.

Thompson PD., Webb M., Becket W., Hinsley T., Jowitt T., Sharrocks AD. & Tassabehji M. (2007) GTF2IRD1 regulates transcription by binding an evolutionarily conserved DNA motif ‘GUCE’ FEBS lett. 581, 1233-1242.

Foxon SP., Metcalfe C., Adams H., Webb M. & Thomas JA. (2007) Electrochemical and Photophysical Properties of DNA metallo-intercalators containing the ruthenium(II)tris(1-pyrazolyl)methane unit. Inorg. Chem., 46, 409-416.

Sturdy A., Naseem R., Finch D., Jowitt T. & Webb M. (2006) Identification and charaterisation of the DNA binding region of BRCA1 Biochem J, 396, 529-535

Carter S., Rimmer S., Rutkaite R. Sturdy A., Swanson L., & Webb M. (2006) Highly branched poly(N-isopropylacrylamide) for use in protein purification. Biomacromolecules, 7, 1124-1130.
Orme R., Douglas I., Rimmer S. & Webb M. (2006). Proteomic analysis of Escherichia coli biofilms reveals the over expression of the outer membrane protein OmpA. Proteomics, 6, 4269-4277.

Finch D. and Webb. M. (2005) Identification and purification of a soluble region in the breast cancer susceptibility protein BRCA2 Protein Expr Purif., 40, 177-182.

Carter S., Rimmer S., Sturdy A. and Webb M. (2005) Highly branched stimuli responsive poly (N-isopropyl acrylamide-co-1,2-propandiol-3-methacrylate with protein binding functionality Macromol. Biosci, 5, 373–378.