PhD Studentship: Molecular Shape-Shifting in the DNA-Damage Response

Background: The proposed project has emerged from a long-standing interest in the signalling and repair functions of the BRCA1 and PALB2 tumour suppressors. Specifically, we have been investigating a novel PALB2 function in activating DNA repair in specific regions of transcriptionally active chromatin through interactions with a chromatin adaptor protein, MRG15. Mechanisms whereby these signals are reversed are still unclear but partly involve inhibition by MRFAP1, one of three closely related but largely unstudied proteins expressed in human cells. These molecules function as molecular ‘shape-shifters’, adopting distinct structural forms each tailored to functionally specific downstream targets. Initial cryo-electron microscopy (cEM) studies show that MRFAP1 forms a remarkable dodecameric ‘nanocage’ which then collapses to a hetero-hexameric complex as it encounters MRG15, displacing PALB2 (and other interacting factors/complexes) to form a new MRG15/MRFAP1/nucleosome assembly of unknown function.

Approaches and goals: The overarching goal is a molecular-level understanding of this important but understudied family of molecules achieved through a multi-disciplinary approach encompassing cell biology, biochemistry, AlphaFold and structural characterisation by X-ray crystallography and cEM. Firstly, this will provide insights into new regulatory mechanisms relevant to several fundamental signalling pathways. However, we also know that increased levels of MRFAP1 are known to be anti-proliferative in cancer cells, and knock-down potentiates effects of some cytotoxic inhibitors, suggesting therapeutic opportunities for both inhibitors and stabilisers of MRFAP1 interactions applicable to cancer and a range of other human diseases.

The project will be supervised by Prof. Steve Smerdon (s.j.smerdon@bham.ac.uk).

Funding notes:
For details of the MIBTP project and programme, visit https://warwick.ac.uk/fac/cross_fac/mibtp/phd/supervisors/SSmerdon/#molecular_shape-shifting
Eligibility and further details are available here:
https://warwick.ac.uk/fac/cross_fac/mibtp/phd/application/ (Scroll to Birmingham section)

References:

Fournier M, et al. Elife. 2022 doi:10.7554/eLife.57736.
Jiang N et al Acta Pharmacol Sin. 2024 doi:10.1038/s41401-023-01211-6.
Hu L, et al. Eur Rev Med Pharmacol Sci. 2018 doi:10.26355/eurrev_201812_16524

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