The cellular abundance of the essential transcription termination factor TTF-I regulates ribosome biogenesis and is determined by MDM2 ubiquitinylation.

Abstract:

:The ARF tumour suppressor stabilizes p53 by negatively regulating the E3 ubiquitin ligase MDM2 to promote cell cycle arrest and cell death. However, ARF is also able to arrest cell proliferation by inhibiting ribosome biogenesis. In greater part this is achieved by targeting the transcription termination factor I (TTF-I) for nucleolar export, leading to an inhibition of both ribosomal RNA synthesis and processing. We now show that in the absence of ARF, TTF-I is ubiquitinylated by MDM2. MDM2 interacts directly with TTF-I and regulates its cellular abundance by targeting it for degradation by the proteasome. Enhanced TTF-I levels inhibit ribosome biogenesis by suppressing ribosomal RNA synthesis and processing, strongly suggesting that exact TTF-I levels are critical for efficient ribosome biogenesis. We further show that concomitant with its ability to displace TTF-I from the nucleolus, ARF inhibits MDM2 ubiquitinylation of TTF-I by competitively binding to a site overlapping the MDM2 interaction site. Thus, both the sub-nuclear localization and the abundance of TTF-I are key regulators of ribosome biogenesis.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Lessard F,Stefanovsky V,Tremblay MG,Moss T

doi

10.1093/nar/gks198

subject

Has Abstract

pub_date

2012-07-01 00:00:00

pages

5357-67

issue

12

eissn

0305-1048

issn

1362-4962

pii

gks198

journal_volume

40

pub_type

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