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Title: An investigation into the regulatory effect of BRCA1 on ribosome biogenesis in breast cancer cells
Author: Johnston, Rebecca
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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RNA Polymerase I (Pol-l) transcribes large ribosomal RNAs (rRNA) which are structural and functional components of a ribosome. rRNA transcription is the first stage of ribosome biogenesis and high level of rRNA synthesis and the concurrent increase in ribosome biogenesis is essential in supporting unrestrained proliferation of cancer cells. Breast cancer susceptibility gene 1 (BRCA 1) is 220 kDa nuclear phosphoprotein and known tumour suppressor which is involved in variety of cellular processes such as DNA damage response, transcriptional regulation, cell cycle control and ubiquitylation. Here, it is reported that BRCA 1 is associated with rDNA repeat and in particular with the regulatory regions of rRNA gene. It was found that BRCA 1 interacts with the basal Pol-1 transcription factors such as upstream binding factor (UBF), selectivity factor-1 (SL 1) and with Pol-1. It was discovered that depletion of BRCA 1 negatively affects rRNA synthesis and the expression of BRCA 1 in BRCA 1 negative cells causes an opposite effect. It was also found that following DNA damage, BRCA 1 occupancy at rDNA repeat is, in most cases, decreased and BRCA 1 interactions with Pol-1 transcription machinery are weakened. We propose that the rDNA associated fraction of BRCA 1 plays a dual role: firstly, it is involved in DNA damage-dependent regulation of Pol-1 transcription, and secondly, it is also a positive regulator of rRNA synthesis which promotes stability or formation of the Pol-1 holoenzyme. Another mechanism which plays a role in cell growth and proliferation is the activation of the nuclear receptor, ER (estrogen receptor). This receptor is the target of several therapeutic drugs however there is an increase in resistance to these drugs. In an attempt to understand the mechanism more clearly, we show that ER activation by 17J3-estradiol results in an increase in the synthesis but not the processing of 47S pre-rRNA. This hormone activation is receptor-dependant as no activation is observed in ER- cells. Our findings demonstrate a previously unidentified link between estrogen signalling and the regulation of ribosome biogenesis and suggest that ER activation of Pol I transcription may be a potential target for treatment of ER+ cancers.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available