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The role of stress-mediated post-translational modifications in the regulation of histone demethylase KDM4A

   School of Biological Sciences

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  Dr K Panov, Dr B Graham  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

We recently discovered that KDM4A is one of the proteins responsible for a specific type of epigenetic modification required for regulation of rRNA transcription activation and showed that a major cellular growth and survival signalling pathway (the PI3K pathway) controls cellular localisation of KDM4A, which is critical for its functions. We also found that when cells are stressed by extremes of temperature, or when DNA is damaged, this can cause the break-down of KDM4A and its removal from the cell.

When the cell recovers from such stress, KDM4A is remade again and can again move to the nucleus where its target chromatin is located. We hypothesise that various signalling cascades are activated either by stress or during the recovery from the effects of stress affect KDM4A functions, thus connecting external signals to chromatin structure. The primary goal of this project is to verify this hypothesis by performing study of KDM4A interactome and KDM4A posttranslational modifications using protein mass-spectrometry.

We recently discovered that histone demethylase KDM4A is required to activate transcription of ribosomal RNA, a key step in ribosome biogenesis that underpins the cell's ability to synthesize proteins. We showed that PI3K pathway controls cellular localization and consequently KDM4A recruitment to rDNA thorough the SGK1 kinase. We also discovered that other stresses (i.e. DNA damage, heat shock) as well as the post-stress recovery affect stability and localisation of KDM4A and these events are linked to KDM4A posttranslational modifications (PTM), in particular ubiquitination and phosphorylation. Based on our preliminary data we hypothesise that KDM4A is part of multisubunit complexes that perform different functions, some of which may be involved in stress-mediated regulation of transcription. Signalling pathways (activated by stress or during recovery from stress), target these complexes, thus regulating the stability, localization and recruitment of KDM4A via various PTMs. The project goal is to identify proteins and signalling pathways involved in stress-mediated regulation of KDM4A stability, localisation and recruitment. To this end we will perform comprehensive studies of KDM4A interactome in stressed and recovering cells, and identify stress mediated PTMs of KDM4A and its interacting partners using protein mass-spectrometry.

Start Date: 1 October 2022

Duration: 3 years

How to apply: Applications must be submitted via:

Note: This project is in competition for DfE funding with a number of other projects. A selection process will determine the strongest candidates across the range of projects, who may then be offered funding for their chosen project.

Funding Notes

Candidates must hold a UK 2.1 Bachelor's degree or qualifications considered to be equivalent by the University.
Candidates must also be normally resident in the UK for the three year period prior to 1 October 2022. For non-EU nationals, the main purpose of residence must not have been to receive full-time education. Non-UK or Irish nationals must also have pre-settled or settled status (EU nationals) or settled status (non-EU nationals).
Full eligibility criteria:
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