Toteva, Tea;
(2021)
Regulation of transcription by SRF and MRTF.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The serum response factor (SRF) is a transcription factor involved in the regulation of cell proliferation and migration. At cytoskeletal genes, SRF acts cooperatively with the actin-regulated myocardin-related transcription factors MRTF-A and MRTF-B. In addition to regulating MRTFs’ subcellular localization, G-actin also controls their nuclear activities. Previous work showed that nuclear accumulation of MRTF-A in the absence of an activating signal is sufficient for its association with genomic loci but not for target gene activation, demonstrating a repressive effect of nuclear actin on MRTF activity. However, the exact mechanism is unclear. The data presented below demonstrates that G-actin interferes with ternary complex formation between SRF and MRTF on DNA. In response to G-actin depletion, MRTF is recruited to target gene promoters and activates gene expression, whereas increasing the concentration of G-actin inhibits MRTF recruitment to target promoters. We used inhibition of the Crm1 nuclear export receptor and reconstitution of MRTF-A/MRTF-B null cells with a constitutively nuclear MRTF- NLS to induce MRTF nuclear accumulation in the absence of an activating signal. Under resting G-actin levels, nuclear MRTF is recruited to target promoters, albeit at reduced levels, and induces non-productive transcription. TTseq and RNAseq experiments demonstrate that while RNA Polymerase II is engaged in elongation, no pre-mRNA accumulates. This inhibited transcriptional state correlates with aberrant Pol II CTD phosphorylation, Mtr4 recruitment and degradation of the nascent transcripts by the nuclear exosome. Inhibition of phosphorylation at Ser7 of the Pol II CTD is sufficient to induce Mtr4-mediated degradation of MRTF- dependent transcripts under induced conditions.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Regulation of transcription by SRF and MRTF |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10128984 |
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