Dr Thomas Schalch E: email@example.com
Dr Harriet Walter E: firstname.lastname@example.org
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.
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.