PR-DUB-nucleosome interactions in cancer

Overview

Supervisors:

Dr Thomas Schalch  E: thomas.schalch@leicester.ac.uk

Dr Harriet Walter  E: hw191@leicester.ac.uk

Project Description:

BRCA1-associated protein 1 (BAP1) is a tumour suppressor protein that antagonizes the silencing activity of polycomb complexes. Its loss is associated with development of malignant mesothelioma, uveal and cutaneous melanoma and other forms of cancer.  BAP1 is a deubiquitinase that forms a complex with ASXL (PR-DUB) to remove ubiquitin modifications from histone H2A.  In this project you will reconstitute PR-DUB and investigate its interaction with nucleosomes and how it is recruited using structural approaches including cryo-EM. To investigate the significance of nucleosome recognition in proliferation of malignant mesothelioma and other cancers caused by BAP1 you will further transduce and analyse cancer cell lines with specific PR-DUB mutants that probe the BAP1-nucleosome interaction. These studies will provide insight into the molecular mechanism of BAP1 and inform future therapeutic approaches to treat aggressive forms of cancer.

This project is a collaboration with Harriet Walter who is an Associate Professor of Medical Oncology at University Hospital Leicester, with expertise in drug development and translation to the clinic. This collaboration leverages our expertise in chromatin structural biology at LISCB with the clinical and therapeutic expertise in treating a broad range of cancers in the Phase 1 setting including mesothelioma.

References: 

1. Scheuermann JC, de Ayala Alonso AG, Oktaba K, Ly-Hartig N, McGinty RK, Fraterman S, Wilm M, Muir TW, Müller J: Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB. Nature 2010, 465:243–247.

2. Louie BH, Kurzrock R: BAP1: Not just a BRCA1-associated protein. Cancer Treatment Reviews 2020, 90:102091.

3. Walter HS, Ahmed S: Targeted therapies in cancer. Surgery (Oxford) 2018, 36:122–127

4. Stirpe A, Guidotti N, Northall S, Kilic S, Hainard A, Vadas O, Fierz B, Schalch T: SUV39 SET domains mediate crosstalk of heterochromatic histone marks. bioRxiv 2020, doi:10.1101/2020.06.30.177071.

Funding

Funding

College of Life Sciences Studentship providing:

  • 3 years stipend at UKRI rates. For 2021/2 this will be £15,609
  • 3 years tuition fees at the Home (UK) rates

Entry requirements

Entry requirements

Applicants are required to hold/or expect to obtain a UK Bachelor Degree 2:1 or better in a relevant subject.

The University of Leicester English language requirements apply where applicable.

Informal enquiries

Informal enquiries

Project / Funding Enquiries: jks43@leicester.ac.uk

Application enquiries to pgradmissions@le.ac.uk

How to apply

How to apply

To submit your application, please use the Apply button at the bottom of the page and select September 2021 from the dropdown menu.

With your application, please include:

  • CV
  • Personal statement explaining your interest in the project, your experience and why we should consider you
  • Degree Certificates and Transcripts of study already completed and if possible transcript to date of study currently being undertaken
  • Evidence of English language proficiency if applicable
  • In the reference section please enter the contact details of your two academic referees in the boxes provided or upload letters of reference if already available
  • In the funding section please specify that you wish to be considered for a MCB Schalch 2021 studentship
  • In the research proposal section please provide the names of the project supervisors and project title (a research proposal is not required)

Eligibility

Eligibility

The studentship is available to UK/EU applicants only.