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p53 is a general repressor of RNA polymerase III transcription
1Institute of Biomedical and Life Sciences, Division of Biochemistry and Molecular Biology, University of Glasgow, Glasgow, G12 8QQ, UK.
Abstract:
p53 is a major tumour suppressor that is inactivated in a large proportion of human cancers. We show that p53 serves as a general repressor of transcription by RNA polymerase (pol) III. It can inhibit the synthesis of a range of essential small cellular RNAs including tRNA, 5S rRNA and U6 snRNA, as well as viral products such as the adenovirus VAI RNA. Fibroblasts derived from p53 knock-out mice display a substantial increase in pol III transcriptional activity. Endogenous cellular p53 is shown to interact with the TATA-binding protein (TBP)-containing general factor TFIIIB, thereby compromising its function severely. However, assembly of TFIIIB into a pre-initiation complex confers substantial protection against the inhibitory effects of p53. Since TFIIIB is an essential determinant of the biosynthetic capacity of cells, its release from repression by p53 may contribute to a loss of growth control during the development of many tumours.
Insights
The tumor suppressor p53 generally represses RNA polymerase III (pol III) transcription. This inhibition of essential small RNAs by p53 may contribute to cancer development by affecting cell growth control.
Area of Science:
- Molecular Biology
- Cancer Biology
- Biochemistry
Background:
- The p53 protein is a critical tumor suppressor frequently inactivated in human cancers.
- RNA polymerase III (pol III) transcribes essential small RNAs, including tRNA, 5S rRNA, and U6 snRNA, vital for cellular function.
- Dysregulation of pol III transcription is implicated in various diseases, including cancer.
Purpose of the Study:
- To investigate the role of p53 in regulating RNA polymerase III transcription.
- To elucidate the mechanism by which p53 affects pol III activity.
- To determine the implications of p53-mediated repression of pol III transcription in cancer.
Main Methods:
- Analysis of pol III transcriptional activity in p53-deficient (knock-out) mouse fibroblasts.
- Investigation of the interaction between p53 and the general transcription factor TFIIIB.
- Assessment of p53's inhibitory effect on TFIIIB function in pre-initiation complex formation.
Main Results:
- p53 acts as a general repressor of pol III transcription, inhibiting the synthesis of various small cellular and viral RNAs.
- Fibroblasts lacking p53 exhibit significantly increased pol III transcriptional activity.
- Endogenous p53 directly interacts with TFIIIB, compromising its function, but complex assembly offers protection.
Conclusions:
- p53 represses pol III transcription by inhibiting the general transcription factor TFIIIB.
- The release of TFIIIB from p53-mediated repression can lead to uncontrolled cell growth, contributing to tumorigenesis.
- Targeting the p53-TFIIIB interaction may offer therapeutic strategies for cancers with p53 inactivation.