Molecular Mechanisms through which Inositol-1,4,5,6-Tetraphosphate and Co-Repressor Proteins Activate Histone Deacetylase Enzymes

The Department of Biochemistry is pleased to offer a funded studentship for October 2012 entry to its Doctor of Philosophy (PhD) programme. The studentship will pay full-time University UK/EU tuition fees for 3.5 years (with the possibility of funding for a further six months subject to performance) and include a tax-free annual maintenance grant worth at least £13,590 a year.

Research Areas and Supervision

Histone deacetylase enzymes (HDACs) play an important role in the regulation of eukaryotic gene expression and are important drug targets for the treatment of various cancers. They act by removing acetyl groups from lysine residues in histone tails resulting in chromatin remodelling. Several class I HDACs (HDACs 1, 2 & 3) are enzymatically inactive until recruited to their cognate corepressor complexes. We have recently determined the crystal structure of the complex between HDAC3 and the SMRT corepressor. This complex was purified from mammalian cells since the bacterially expressed proteins do not interact.

This structure shows two remarkable features. First, on forming a complex with HDAC3 the SMRT protein undergoes a significant structural rearrangement. Second, an unexpected Ins(1,4,5,6)P4 molecule is located in a highly basic pocket, at the interface between SMRT and HDAC3. The Ins(1,4,5,6)P4 acts as an ‘intermolecular glue’. Mutations in residues that bind the Ins(1,4,5,6)P4 suggest that it plays a key role in the activation of HDAC3. However, the exact mechanism of activation remain to be elucidated and represent the core of this project. There is considerable interest since the Ins(1,4,5,6)P4 binding site has the potential to be a drug target for the inhibition of class I HDAC activity.

This studentship will provide excellent training in structural biology and enzymology. Hard working, independent minded. and enthusiastic applicants are encouraged to apply.

Selected References

Watson PJ, Fairall L, Santos GM, Schwabe JW. (2012) structure of HDAC3 bound to co-repressor and inositol tetraphosphate. Nature, 481, 335-340.

Oberoi J, Fairall L, Watson PJ, Yang JC, Czimmerer Z, Kampmann T, Goult BT, Greenwood JA, Gooch JT, Kallenberger BC, Nagy L, Neuhaus D, Schwabe JW (2011) Structural basis for the assemblyof the SMRT/NCoR core transcriptional repression machinery. Nature Struct. Mol. Biol., 18, 177-184.

Entry Requirements

Applicants must have a first-class or high upper second-class honours degree (or equivalent qualification) in a relevant discipline and meet the University's standard English language entry requirements.

This studentship is open to suitable UK/EU and International (i.e., outside the EU) applicants. Please note though that the award covers tuition fees at the UK/EU rate only. International applicants (and those not eligible to pay UK/EU tuition fees) must demonstrate at the time of their application that they can fund the difference in tuition fee rates.

The studentship is for full-time study only and applicants must be able to commence their studies in October 2012.

Informal Enquiries

Informal enquiries are welcomed - please contact:

• Dr Mohammed El-Mezgueldi
• mem16@le.ac.uk
• Tel. +44 (0)116 229 7102

Apply Now

To apply, simply follow our three-point checklist:

1. Draft a brief personal statement explaining why you would like to work in this area and describing any relevant research experience (including any research projects that you have undertaken - for example, as part of a previous degree - and listing any academic work you have published or which is currently in press awaiting publication). Your personal statement should be no more than 1,000 words.
2. Prepare your supporting documents - including a full Curriculum Vitae
3. Submit your online application or apply by post

The studentship will remain open until filled - however early application is encouraged.

IMPORTANT - In the Fees and Financial Support section of the application, you must state that you wish to be considered for this "PhD Studentship Biochemistry Ref. MBSP-12/08"

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