Journal Article
. 2019 Sep; 92(3):385-396.

The Short N-Terminal Repeats of Transcription Termination Factor 1 Contain Semi-Redundant Nucleolar Localization Signals and P19-ARF Tumor Suppressor Binding Sites

Joël Boutin 1 Frédéric Lessard 1 Michel G Tremblay 1 Tom Moss 1 
Affiliations
  • PMID: 31543703
  •     43 References

Abstract

The p14/p19ARF (ARF) tumor suppressor provides an important link in the activation of p53 (TP53) by inhibiting its targeted degradation via the E3 ligases MDM2/HDM2. However, ARF also limits tumor growth by directly inhibiting ribosomal RNA synthesis and processing. Initial studies of the ARF tumor suppressor were compounded by overlap between the INK4A and ARF genes encoded by the CDKN2A locus, but mouse models of pure ARF-loss and its inactivation in human cancers identified it as a distinct tumor suppressor even in the absence of p53. We previously demonstrated that both human and mouse ARF interact with Transcription Termination Factor 1 (TTF1, TTF-I), an essential factor implicated in transcription termination and silencing of the ribosomal RNA genes. Accumulation of ARF upon oncogenic stress was shown to inhibit ribosomal RNA synthesis by depleting nucleolar TTF1. Here we have mapped the functional nucleolar localization sequences (NoLS) of mouse TTF1 and the sequences responsible for interaction with ARF. We find that both sequences lie within the 25 amino acid N-terminal repeats of TTF1. Nucleolar localization depends on semi-redundant lysine-arginine motifs in each repeat and to a minor extent on binding to target DNA sequences by the Myb homology domain of TTF1. While nucleolar localization of TTF1 predominantly correlates with its interaction with ARF, NoLS activity and ARF binding are mediated by distinct sequences within each N-terminal repeat. The data suggest that the N-terminal repeats of mouse TTF1, and by analogy those of human TTF1, cooperate to mediate both nucleolar localization and ARF binding.

Keywords: Nucleolar localization sequence; RNA polymerase I; Transcription Termination Factor 1; p19/p14ARF; ribosome biogenesis; tumor suppressor.

Other Links

Free PMC article 
Targeting RNA polymerase I with an oral small molecule CX-5461 inhibits ribosomal RNA synthesis and solid tumor growth.
Denis Drygin, Amy Lin, +15 authors, William G Rice.
Cancer Res, 2010 Dec 17; 71(4). PMID: 21159662
Highly Cited.
Slug regulates E-cadherin repression via p19Arf in prostate tumorigenesis.
Yingqiu Xie, Shenji Liu, +6 authors, Zhenbang Chen.
Mol Oncol, 2014 Jun 10; 8(7). PMID: 24910389    Free PMC article.
Nucleolar targeting: the hub of the matter.
Edward Emmott, Julian A Hiscox.
EMBO Rep, 2009 Feb 21; 10(3). PMID: 19229283    Free PMC article.
Highly Cited. Review.
Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53.
Megan J Bywater, Gretchen Poortinga, +20 authors, Ross D Hannan.
Cancer Cell, 2012 Jul 14; 22(1). PMID: 22789538    Free PMC article.
Highly Cited.
Transfection of mammalian cells using linear polyethylenimine is a simple and effective means of producing recombinant adeno-associated virus vectors.
Sharon E Reed, Elizabeth M Staley, +2 authors, Gregory E Tullis.
J Virol Methods, 2006 Sep 05; 138(1-2). PMID: 16950522
Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses.
Carlos P Rubbi, Jo Milner.
EMBO J, 2003 Nov 12; 22(22). PMID: 14609953    Free PMC article.
Highly Cited.
Differential p53-independent outcomes of p19(Arf) loss in oncogenesis.
Zhenbang Chen, Arkaitz Carracedo, +9 authors, Pier Paolo Pandolfi.
Sci Signal, 2009 Aug 20; 2(84). PMID: 19690330    Free PMC article.
Tumour suppressor gene mutations in humans and mice: parallels and contrasts.
M L Hooper.
EMBO J, 1998 Dec 08; 17(23). PMID: 9843483    Free PMC article.
Review.
The ARF tumor suppressor controls ribosome biogenesis by regulating the RNA polymerase I transcription factor TTF-I.
Frédéric Lessard, Françoise Morin, +4 authors, Tom Moss.
Mol Cell, 2010 Jun 02; 38(4). PMID: 20513429
Conditional inactivation of Upstream Binding Factor reveals its epigenetic functions and the existence of a somatic nucleolar precursor body.
Nourdine Hamdane, Victor Y Stefanovsky, +6 authors, Tom Moss.
PLoS Genet, 2014 Aug 15; 10(8). PMID: 25121932    Free PMC article.
Different domains of the murine RNA polymerase I-specific termination factor mTTF-I serve distinct functions in transcription termination.
R Evers, A Smid, +2 authors, I Grummt.
EMBO J, 1995 Mar 15; 14(6). PMID: 7720715    Free PMC article.
The chromatin remodeling complex NoRC targets HDAC1 to the ribosomal gene promoter and represses RNA polymerase I transcription.
Yonggang Zhou, Raffaella Santoro, Ingrid Grummt.
EMBO J, 2002 Aug 29; 21(17). PMID: 12198165    Free PMC article.
Ribosome biogenesis and cancer: basic and translational challenges.
Xosé R Bustelo, Mercedes Dosil.
Curr Opin Genet Dev, 2017 Nov 04; 48. PMID: 29100209
Review.
Targeting the nucleolus for cancer intervention.
Jaclyn E Quin, Jennifer R Devlin, +3 authors, Ross D Hannan.
Biochim Biophys Acta, 2014 Jan 07; 1842(6). PMID: 24389329
Highly Cited. Review.
Nucleolar Arf tumor suppressor inhibits ribosomal RNA processing.
Masataka Sugimoto, Mei-Ling Kuo, Martine F Roussel, Charles J Sherr.
Mol Cell, 2003 Mar 07; 11(2). PMID: 12620229
Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation.
Koji Itahana, Krishna P Bhat, +4 authors, Yanping Zhang.
Mol Cell, 2003 Nov 26; 12(5). PMID: 14636574
Highly Cited.
The Ribosome Biogenesis-Cancer Connection.
Marianna Penzo, Lorenzo Montanaro, Davide Treré, Massimo Derenzini.
Cells, 2019 Jan 18; 8(1). PMID: 30650663    Free PMC article.
Highly Cited. Review.
Ribosome biogenesis in cancer: new players and therapeutic avenues.
Joffrey Pelletier, George Thomas, Siniša Volarević.
Nat Rev Cancer, 2017 Dec 02; 18(1). PMID: 29192214
Highly Cited. Review.
The differential impact of p16(INK4a) or p19(ARF) deficiency on cell growth and tumorigenesis.
Norman E Sharpless, Matthew R Ramsey, +2 authors, Ronald A DePinho.
Oncogene, 2004 Jan 16; 23(2). PMID: 14724566
Distinct turnover of alternatively spliced isoforms of the RET kinase receptor mediated by differential recruitment of the Cbl ubiquitin ligase.
Rizaldy P Scott, Susanna Eketjäll, Helena Aineskog, Carlos F Ibáñez.
J Biol Chem, 2005 Jan 29; 280(14). PMID: 15677445
lncRNA maturation to initiate heterochromatin formation in the nucleolus is required for exit from pluripotency in ESCs.
Nataša Savić, Dominik Bär, +9 authors, Raffaella Santoro.
Cell Stem Cell, 2014 Dec 07; 15(6). PMID: 25479748
The chromatin remodeling complex NoRC and TTF-I cooperate in the regulation of the mammalian rRNA genes in vivo.
Attila Németh, Ralf Strohner, Ingrid Grummt, Gernot Längst.
Nucleic Acids Res, 2004 Aug 05; 32(14). PMID: 15292447    Free PMC article.
p53-independent functions of the p19(ARF) tumor suppressor.
J D Weber, J R Jeffers, +5 authors, G P Zambetti.
Genes Dev, 2000 Sep 20; 14(18). PMID: 10995391    Free PMC article.
Highly Cited.
DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response.
Laureen Colis, Karita Peltonen, +5 authors, Marikki Laiho.
Oncotarget, 2014 Jun 24; 5(12). PMID: 24952786    Free PMC article.
P19ARF and RasV¹² offer opposing regulation of DHX33 translation to dictate tumor cell fate.
Yandong Zhang, Anthony J Saporita, Jason D Weber.
Mol Cell Biol, 2013 Feb 13; 33(8). PMID: 23401854    Free PMC article.
Small molecule BMH-compounds that inhibit RNA polymerase I and cause nucleolar stress.
Karita Peltonen, Laureen Colis, +6 authors, Marikki Laiho.
Mol Cancer Ther, 2014 Oct 04; 13(11). PMID: 25277384    Free PMC article.
A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine.
O Boussif, F Lezoualc'h, +4 authors, J P Behr.
Proc Natl Acad Sci U S A, 1995 Aug 01; 92(16). PMID: 7638184    Free PMC article.
Highly Cited.
The amino-terminal domain of the transcription termination factor TTF-I causes protein oligomerization and inhibition of DNA binding.
E E Sander, S W Mason, C Munz, I Grummt.
Nucleic Acids Res, 1996 Oct 01; 24(19). PMID: 8871544    Free PMC article.
Putting p53 in Context.
Edward R Kastenhuber, Scott W Lowe.
Cell, 2017 Sep 09; 170(6). PMID: 28886379    Free PMC article.
Highly Cited. Review.
Rare ribosomopathies: insights into mechanisms of cancer.
Anna Aspesi, Steven R Ellis.
Nat Rev Cancer, 2019 Jan 24; 19(4). PMID: 30670820
Highly Cited. Review.
Solution structure of the p53 regulatory domain of the p19Arf tumor suppressor protein.
E L DiGiammarino, I Filippov, +2 authors, R W Kriwacki.
Biochemistry, 2001 May 01; 40(8). PMID: 11327858
The Human RNA Polymerase I Transcription Terminator Complex Acts as a Replication Fork Barrier That Coordinates the Progress of Replication with rRNA Transcription Activity.
Yufuko Akamatsu, Takehiko Kobayashi.
Mol Cell Biol, 2015 Mar 18; 35(10). PMID: 25776556    Free PMC article.
The cellular abundance of the essential transcription termination factor TTF-I regulates ribosome biogenesis and is determined by MDM2 ubiquitinylation.
Frédéric Lessard, Victor Stefanovsky, Michel G Tremblay, Tom Moss.
Nucleic Acids Res, 2012 Mar 03; 40(12). PMID: 22383580    Free PMC article.
The Ink4a/Arf locus operates as a regulator of the circadian clock modulating RAS activity.
Rukeia El-Athman, Nikolai N Genov, +9 authors, Angela Relógio.
PLoS Biol, 2017 Dec 08; 15(12). PMID: 29216180    Free PMC article.
The ARF tumor suppressor in acute leukemias: insights from mouse models of Bcr-Abl-induced acute lymphoblastic leukemia.
Richard T Williams, Charles J Sherr.
Adv Exp Med Biol, 2007 Aug 19; 604. PMID: 17695724
Review.
Defining the molecular basis of Arf and Hdm2 interactions.
B Bothner, W S Lewis, +3 authors, R W Kriwacki.
J Mol Biol, 2001 Nov 24; 314(2). PMID: 11718560
New Roles for the Nucleolus in Health and Disease.
Lorena Núñez Villacís, Mei S Wong, +3 authors, Katherine M Hannan.
Bioessays, 2018 Apr 01; 40(5). PMID: 29603296
Review.
The INK4a/ARF network in tumour suppression.
C J Sherr.
Nat Rev Mol Cell Biol, 2001 Oct 05; 2(10). PMID: 11584300
Highly Cited. Review.
A mutation hotspot at the p14ARF splice site.
Mark Harland, Claire F Taylor, +9 authors, Julia A Newton Bishop.
Oncogene, 2005 Apr 28; 24(28). PMID: 15856016
Depletion of the cisplatin targeted HMGB-box factor UBF selectively induces p53-independent apoptotic death in transformed cells.
Nourdine Hamdane, Chelsea Herdman, +3 authors, Tom Moss.
Oncotarget, 2015 Sep 01; 6(29). PMID: 26317157    Free PMC article.
The ARF/p53 pathway.
C J Sherr, J D Weber.
Curr Opin Genet Dev, 2000 Feb 19; 10(1). PMID: 10679383
Highly Cited. Review.
The ARF tumor suppressor prevents chromosomal instability and ensures mitotic checkpoint fidelity through regulation of Aurora B.
Eric M C Britigan, Jun Wan, +2 authors, Beth A Weaver.
Mol Biol Cell, 2014 Jul 25; 25(18). PMID: 25057018    Free PMC article.
Tumor suppression by Ink4a-Arf: progress and puzzles.
Scott W Lowe, Charles J Sherr.
Curr Opin Genet Dev, 2003 Feb 08; 13(1). PMID: 12573439
Highly Cited. Review.