Dr Clare Davies PhD, B.Med.Sc

Dr Clare Davies

Institute of Cancer and Genomic Sciences
Senior Birmingham Fellow

Contact details

Address
College of Medical and Dental Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT
UK

Clare Davies is a Senior Fellow in the Institute of Cancer and Genomic Sciences, where her research is focused on understanding the role of PRMTs, enzymes that catalyse methylation of arginine residues, in cancer pathogenesis. This is important as inhibitors to specific PRMTs are in pre-clinical development for cancer therapy.

Clare started her research group in 2012 as a Birmingham Fellow and her approaches involve understanding the role of PRMTs from the molecular level to the whole animal, by using a combination of cell biology, protein-biochemistry and mouse genetics approaches. She has attracted highly competitive funding from CRUK, the MRC, Breast Cancer Now and Astra Zeneca, and her most recent work focusing on breast cancer as a model, has led to publications in Molecular Cell and Cell Reports.

Qualifications

  • PhD in Cancer Biology (2003)
  • B.Med.Sci (Hons) (1998)

Biography

Clare Davies qualified in 1998 with a Bachelor of Medical Science (B.Med.Sc) from the University of Birmingham, and continued her studies in Birmingham obtaining a PhD in Cancer Biology at the School of Cancer Sciences. 

Clare was then awarded a CRUK Post-Doctoral Fellowship to work with Dr. Axel Behrens at the CRUK-London Research Institute (LRI) investigating novel mechanisms of gene expression in cancer. It was here that she first encountered arginine methylation and realised that there was still much to be discovered about this protein modification. She then joined Dr. Cathy Tournier’s lab at the University of Manchester where she built on her expertise studying cancer development in vivo using genetically altered mice. 

In October 2012, Clare was awarded a Birmingham Fellowship to join the Institute of Cancer and Genomic Sciences and initiate her own research group investigating the role of arginine methylation in cancer pathogenesis. She has since been awarded an MRC New Investigator Award and a CRUK Programme Foundation Award to continue her research.

Teaching

  • Lecturer for the BSc Biomedical Sciences programme (formally B.Med.Sc).
  • Lecturer for MRes Cancer Sciences (Genomics Module).
  • Tutorials for BSc Biomedical Sciences, MRes Cancer Sciences and MBChB programmes.
  • Deputy module co-ordinator for Genomic Module, MRes Cancer Sciences.

Postgraduate supervision

Clare has supervised a number of PhD and postgraduate Masters students to completion. Her first PhD student obtained a Molecular Cell publication and a EMBO Long-term Fellowship to Postdoc at Harvard University. Many of Clare’s Masters students are now enrolled on PhD programmes.

She is always happy to hear from talented and motivated students that are not afraid of hard work, and will benefit from a highly supportive and mentoring environment. 

If you are interested in studying any of these subject areas please contact Clare on the contact details above, or for any general doctoral research enquiries, please email: dr@contacts.bham.ac.uk or call +44 (0)121 414 5005.

Research

Arginine methylation – a new player in cancer pathogenesis

Protein modifications expand the functional diversity of the proteome enabling dynamic modulation of cellular processes, but are often deregulated during cancer pathogenesis. Arginine methylation, catalysed by protein arginine methyltransferases (PRMTs), was identified over 45 years ago, however the significance of this modification for oncogenesis and malignant progression is only just becoming apparent. In particular, expression of many PRMTs correlates with a poorer cancer prognosis and has thus attracted significant attention as a novel drug target. Despite this potential, the mechanisms by which PRMTs contribute to cancer progression is largely unknown. The Davies lab aims to increase our understanding into the biology of PRMTs and arginine methylation.  Using breast cancer as a model, the questions we are currently addressing are:

1) How is PRMT5 regulating the DNA damage response?

We have recently described a role for PRMT5 in homologous recombination-mediated repair of double strand breaks through the methylation of RUVBL1 (Clarke et al., Molecular Cell). We are now taking a variety of molecular, epigenetic, cell biology and proteomic approaches to expand these findings and to fully investigate the importance of arginine methylation in DNA repair and drug resistance.

2) What is the mechanism by which PRMT5 controls the function of breast cancer stem cells?

Breast cancer stem cells (BCSCs) are thought to be the cell of tumour initiation and responsible for disease relapse and metastatic spread. Drug targeting this tumour population is particular challenging as they are relatively resistant to conventional chemotherapies. We have shown that PRMT5 is a key regulator of BCSCs, and that depletion of PRMT5 in a murine tumour model significantly decreased the proportion of BCSCs (Chiang et al. Cell Reports). We found that PRMT5 epigenetically regulates the BCSC transcriptome, leading to gene activation and repression. Future questions will address the other mechanism by which PRMT5 regulates BCSC, and how the epigenome and transcriptome is influenced by arginine methylation.

3) Do PRMTs initiate and/or facilitate cancer progression and can a cancer arginine methylome be identified?

Deletion of PRMT1/5 is embryonic lethal, therefore we use conditional knockout strains of PRMT1 and PRMT5 to study the role of PRMTs for malignant progression within a multicellular organism. We are currently studying mammary gland tumours through intra-ductal delivery of Cre-expressing viruses enabling recombination specially within the ductal tree. In parallel, we are using quantitative proteomics to identify the breast cancer-specific substrate repertoire of PRMT1 and PRMT5.

To address all of these questions, the Davies lab takes a multidisciplinary approach that includes molecular and cell biology, flow cytomoetry, quantitative proteomics, protein biochemistry (methylation assays, immunoprecipitations), genomic analysis (RNA-Seq and ChIP-Seq), single cell analysis, analysis of patient sample by IHC and functional assays, microscopy and animal models of cancer (genetically engineered, cell line xenografts and patient-derived xenografts (PDXs)). 

Research Groups and Centres: 

Birmingham Centre for Genome Biology (BCGB) https://www.birmingham.ac.uk/research/activity/mds/centres/genome-biology/index.aspx

Twitter: @DaviesLab_CH3

Other activities

Member of the Biochemical Society

Publications

Chiang K, Zielinska AE, Shaaban AM, Sanchez-Bailon MP, Jarrold J, Clarke TL, Zhang J, Francis A, Jones LJ, Smith S, Barbash O, Guccione E, Farnie G, Smalley MJ, Davies CC (2017). PRMT5 is a critical regulator of breast cancer stem cells via histone methylation and FOXP1 expression. Cell Rep. 21(12):3498-3513.

Clarke TL, Sanchez-Bailon MP, Chiang K, Reynolds JJ, Herrero-Ruiz J, Bandeiras TM, Matias PM, Maslen SL, Skehel JM, Stewart GS, Davies CC (2017). PRMT5-dependent methylation of the TIP60 coactivator RUVBL1 is a key regulator of homologous recombination.  Molecular Cell. 65(5):900-916.e7.

McNee G, Eales KL, Wei W, Williams DS, Barkhuizen A, Bartlett DB, Essex S, Anandram S, Filer A, Moss PA, Pratt G, Basu S, Davies CC, Tennant DA (2017). Citruillination of Histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma. Leukemia;31(2):373-381

Carneiro DG, Clarke T, Davies CC, Bailey D (2016). Identifying novel protein interactions: Proteomic methods, optimisation approaches and data analysis pipelines. Methods. 15;95:46-54. doi: 10.1016/j.ymeth.2015.08.022.

Davies CC, Harvey E, McMahon R, Finegan KG, Connor F, Davies RJ, Tuveson DA, Tournier C (2014) Conditional deletion of mkk4 and mkk7 cooperates with KrasG12D expression to accelerate pancreatic ductal adenocarcinoma in mice. Cancer Research 74 (12), 3344-56.
 
Davies CC and Behrens A (2013) Arginine methylation: Making its mark on AP-1 gene activation. Cell Cycle 12:15, 2333–2334.  
 
Davies CC, Chakraborty A, Diefenbacher ME, Skehel M, and Behrens A (2013) Arginine methylation of the c-Jun co-activator RACO-1 is required for c-Jun/AP-1 activation. The EMBO Journal 32, 1556 – 1567.

Davies C and Tournier C (2012). Exploring the function of the JNK (c-Jun N-terminal kinase) signalling pathway in physiological processes to design novel therapeutic stratagies. Biochem Soc Trans. (40):85-9. 

Davies CC, Chakraborty A, Cipriani F, Haigh K, Haigh JJ and Behrens A (2010). RACO-1 links AP-1 activity to growth
factor signalling.
 Nature Cell Biology, (10): 963-72 *Signalling Gatway Featured Article of the Week 

Davies CC, Mak TW, Young LS, Eliopoulos AG (2005). TRAF6 is required for TRAF2 dependent CD40 signal
transduction in nonhemopoietic cells.
 Mol. Cell Biol. (25): 9806-19 

Davies CC, Bem D, Young LS, Eliopoulos AG (2005). NF-kB overrides the apoptotic program of TNF receptor 1 but
not CD40 in carcinoma cells.
 Cell Signal (17): 723-38 

Davies CC, Mason J, Wakelam MJ, Young LS, Eliopoulos AG (2004). Inhibition of PI3K and ERK MAPK-regulated protein synthesis reveals the pro-apoptotic properties of CD40 ligation in carcinoma cells. J Biol Chem. (279): 1010-19 

View all publications in research portal