Brf1 loss and not overexpression disrupts tissues homeostasis in the intestine, liver and pancreas

Liko, D. et al. (2019) Brf1 loss and not overexpression disrupts tissues homeostasis in the intestine, liver and pancreas. Cell Death and Differentiation, 26(12), pp. 2535-2550. (doi: 10.1038/s41418-019-0316-7) (PMID:30858608) (PMCID:PMC6861133)

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Abstract

RNA polymerase III (Pol-III) transcribes tRNAs and other small RNAs essential for protein synthesis and cell growth. Pol-III is deregulated during carcinogenesis; however, its role in vivo has not been studied. To address this issue, we manipulated levels of Brf1, a Pol-III transcription factor that is essential for recruitment of Pol-III holoenzyme at tRNA genes in vivo. Knockout of Brf1 led to embryonic lethality at blastocyst stage. In contrast, heterozygous Brf1 mice were viable, fertile and of a normal size. Conditional deletion of Brf1 in gastrointestinal epithelial tissues, intestine, liver and pancreas, was incompatible with organ homeostasis. Deletion of Brf1 in adult intestine and liver induced apoptosis. However, Brf1 heterozygosity neither had gross effects in these epithelia nor did it modify tumorigenesis in the intestine or pancreas. Overexpression of BRF1 rescued the phenotypes of Brf1 deletion in intestine and liver but was unable to initiate tumorigenesis. Thus, Brf1 and Pol-III activity are absolutely essential for normal homeostasis during development and in adult epithelia. However, Brf1 overexpression or heterozygosity are unable to modify tumorigenesis, suggesting a permissive, but not driving role for Brf1 in the development of epithelial cancers of the pancreas and gut.

Item Type:Articles
Additional Information:This work was funded by Cancer Research UK grants: A10419, A17196, A12481, A21139, A11650. JRPK and OJS were also funded by an ERC Starting Grant (ColonCan – 311301). KJC was funded by the Royal Society Dorothy Hodgkin Fellowship (DH100099). TGB. was funded by Wellcome Trust (WT107492Z). CJ, KD and AEW were funded by an MRC programme grant.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Blyth, Professor Karen and Bryson, Miss Sheila and King, Dr Ayala and Bird, Dr Thomas and Liko, Dr Dritan and Mitchell, Mrs Louise and Campbell, Dr Kirsteen and Ridgway, Dr Rachel and Strathdee, Dr Douglas and Morton, Professor Jen and Stevenson, Dr David and Sansom, Professor Owen
Authors: Liko, D., Mitchell, L., Campbell, K., Ridgway, R., Jones, C., Dudek, K., King, A., Bryson, S., Stevenson, D., Blyth, K., Strathdee, D., Morton, J. P., Bird, T., Knight, J. R.P., Willis, A. E., and Sansom, O. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Death and Differentiation
Publisher:Springer Nature
ISSN:1350-9047
ISSN (Online):1476-5403
Published Online:11 March 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Cell Death and Differentiation 26(12): 2535-2550
Publisher Policy:Reproduced under a Creative Commons license

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