| Autor: |
Johnston R; School of Biological Sciences, Queen's University Belfast, Belfast, BT9 7BL, UK., D'Costa Z; The Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL, UK.; Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK., Ray S; School of Biological Sciences, Queen's University Belfast, Belfast, BT9 7BL, UK.; Krebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, S10 2TN, UK., Gorski J; The Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL, UK., Harkin DP; The Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL, UK., Mullan P; The Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL, UK., Panov KI; School of Biological Sciences, Queen's University Belfast, Belfast, BT9 7BL, UK.; The Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL, UK. |
| Abstrakt: |
The unrestrained proliferation of cancer cells requires a high level of ribosome biogenesis. The first stage of ribosome biogenesis is the transcription of the large ribosomal RNAs (rRNAs); the structural and functional components of the ribosome. Transcription of rRNA is carried out by RNA polymerase I (Pol-I) and its associated holoenzyme complex.Here we report that BRCA1, a nuclear phosphoprotein, and a known tumour suppressor involved in variety of cellular processes such as DNA damage response, transcriptional regulation, cell cycle control and ubiquitylation, is associated with rDNA repeats, in particular with the regulatory regions of the rRNA gene.We demonstrate that BRCA1 interacts directly with the basal Pol-I transcription factors; upstream binding factor (UBF), selectivity factor-1 (SL1) as well as interacting with RNA Pol-I itself. We show that in response to DNA damage, BRCA1 occupancy at the rDNA repeat is decreased and the observed BRCA1 interactions with the Pol-I transcription machinery are weakened.We propose, therefore, that there is a rDNA associated fraction of BRCA1 involved in DNA damage dependent regulation of Pol-I transcription, regulating the stability and formation of the Pol-I holoenzyme during initiation and/or elongation in response to DNA damage. |
