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Rodriguez Pastrana, I, 2023. The role of p53 cofactor JMY in the regulation of gene expression in human tumours during DNA damage. PhD, Nottingham Trent University.
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Abstract
The tumour suppressor p53 is a nuclear transcription factor that orchestrates a myriad of cellular pathways, including cell cycle arrest, DNA repair, and apoptosis in response to stress. JMY is a DNA damage responsive actin nucleator which exhibits dynamic cellular localisation depending on different stressors. Upon specific genotoxic stress conditions, JMY undergoes nuclear accumulation, where it enhances p53 transcriptional activity. To expand our understanding of the transcriptional regulatory role of nuclear JMY, we performed a transcriptomic analysis to identify JMY-mediated changes in gene expression during etoposide-induced DNA damage. Our findings reveal novel functions of nuclear JMY in DNA repair, paraspeckle biogenesis, and alternative splicing. Notably, the absence of JMY compromises the expression of p53-dependent targets involved in DNA repair, leading to impaired activation of the DNA damage response and the accumulation of DNA lesions. Moreover, we demonstrate that JMY’s Arp2/3- dependent actin nucleation role promotes the p53-dependent expression of DNA repair factors and enhances DNA repair. Remarkably, the loss of JMY sensitises tumour cells to chemotherapeutic agents, reducing cell survival and proliferation. These results are reflected in human tumours where lower JMY levels are correlated with increased overall patient survival.
Additionally, our findings demonstrate that JMY impacts on the p53-dependent transcriptional regulation of lncRNA NEAT1_2 and thus paraspeckle biogenesis. Although the mechanisms are incompletely understood, we observe that the disruption of paraspeckles increases tumour cell sensitivity to DNA damaging agents. Furthermore, our study establishes that JMY is required for the expression of U2 snRNP-related splicing factors and shows that JMY modulates alternative splicing during DNA damage. Collectively, these results provide further insights into the transcriptional regulatory role of nuclear JMY within human tumour cells during DNA damage and can lead to potential clinical opportunities to target key cellular pathways such as the p53 signalling response and alternative splicing.
| Item Type: | Thesis |
|---|---|
| Creators: | Rodriguez Pastrana, I. |
| Contributors: | Name Role NTU ID ORCID |
| Date: | July 2023 |
| Rights: | The copyright in this work is held by the author. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed to the author. |
| Divisions: | Schools > School of Science and Technology |
| Record created by: | Jeremy Silvester |
| Date Added: | 28 Jun 2024 13:32 |
| Last Modified: | 28 Jun 2024 13:32 |
| URI: | https://irep.ntu.ac.uk/id/eprint/51650 |
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