title: The C-terminus of Utp4, mutated in childhood cirrhosis, is essential for ribosome biogenesis.
abstract: The small subunit (SSU) processome is a large ribonucleoprotein that is required for maturation of the 18S rRNA of the ribosome. Recently, a missense mutation in the C-terminus of an SSU processome protein, Utp4/Cirhin, was reported to cause North American Indian childhood cirrhosis (NAIC). In this study, we use Saccharomyces cerevisiae as a model to investigate the role of the NAIC mutation in ribosome biogenesis. While we find that the homologous NAIC mutation does not cause growth defects or aberrant ribosome biogenesis in yeast, we show that an intact C-terminus of Utp4 is required for cell growth and maturation of the 18S and 25S rRNAs. A protein-protein interaction map of the seven-protein t-Utp subcomplex of which Utp4 is a member shows that Utp8 interacts with the C-terminus of Utp4 and that this interaction is essential for assembly of the SSU processome and for the function of Utp4 in ribosome biogenesis. Furthermore, these results allow us to propose that NAIC may be caused by dysfunctional pre-ribosome assembly due to the loss of an interaction between the C-terminus of Utp4/Cirhin and another SSU processome protein.
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Emily F
authors.initials: EF
authors.lastname: Freed
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Baserga
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D021122:Protein Subunits / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D020798:Two-Hybrid System Techniques
chemical_list: D021122:Protein Subunits; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D029701:Saccharomyces cerevisiae Proteins; C470475:UTP4 protein, human; C552251:Utp4 protein, S cerevisiae; C524393:Utp8 protein, S cerevisiae
references.citation: Trends Biochem Sci. 2007 Dec;32(12):530-1
references.pmid: 17980603
references.citation: Science. 2008 Jun 13;320(5882):1465-70
references.pmid: 18467557
references.citation: Science. 2008 Oct 3;322(5898):56-7
references.pmid: 18832636
references.citation: Genes Dev. 2004 Oct 15;18(20):2506-17
references.pmid: 15489292
references.citation: Nature. 2000 Feb 10;403(6770):623-7
references.pmid: 10688190
references.citation: Nature. 2002 Jun 27;417(6892):967-70
references.pmid: 12068309
references.citation: Cell Mol Life Sci. 2008 Aug;65(15):2334-59
references.pmid: 18408888
references.citation: Exp Cell Res. 2004 May 15;296(1):43-50
references.pmid: 15120992
references.citation: Mol Cell Biol. 1997 Oct;17(10):5803-12
references.pmid: 9315638
references.citation: Trends Biochem Sci. 1999 Nov;24(11):437-40
references.pmid: 10542411
references.citation: Bioinformatics. 2007 Nov 1;23(21):2947-8
references.pmid: 17846036
references.citation: Mol Cell Biol. 2003 Dec;23(23):8519-27
references.pmid: 14612397
references.citation: Methods Enzymol. 2007;425:283-316
references.pmid: 17673089
references.citation: Gene. 1995 Apr 14;156(1):119-22
references.pmid: 7737504
references.citation: RNA. 2009 Mar;15(3):406-19
references.pmid: 19141608
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D229-32
references.pmid: 18978020
references.citation: Science. 2008 Oct 3;322(5898):104-10
references.pmid: 18719252
references.citation: Exp Cell Res. 2005 Dec 10;311(2):218-28
references.pmid: 16225863
references.citation: Genetics. 1996 Dec;144(4):1425-36
references.pmid: 8978031
references.citation: Exp Cell Res. 2009 Nov 1;315(18):3086-98
references.pmid: 19732766
references.citation: Mol Cell. 2004 Jan 30;13(2):225-39
references.pmid: 14759368
references.citation: Mol Cell Biol. 2007 Aug;27(15):5414-29
references.pmid: 17515605
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1143-7
references.pmid: 10655498
references.citation: Mol Cell Biol. 2006 Sep;26(17):6656-63
references.pmid: 16914746
references.citation: Yeast. 2000 Jun 30;16(9):857-60
references.pmid: 10861908
references.citation: Genes Dev. 2007 Aug 15;21(16):2041-54
references.pmid: 17699751
references.citation: Am J Hum Genet. 2002 Dec;71(6):1443-9
references.pmid: 12417987
references.citation: Med Sci (Paris). 2007 Nov;23(11):1002-7
references.pmid: 18021715