title: Leaky ribosomal scanning in mammalian genomes: significance of histone H4 alternative translation in vivo.
abstract: Like alternative splicing, leaky ribosomal scanning (LRS), which occurs at suboptimal translational initiation codons, increases the physiological flexibility of the genome by allowing alternative translation. Comprehensive analysis of 22 208 human mRNAs indicates that, although the most important positions relative to the first nucleotide of the initiation codon, -3 and +4, are usually such that support initiation (A-3 = 42%, G-3 = 36% and G+4 = 47%), only 37.4% of the genes adhere to the purine (R)-3/G+4 rule at both positions simultaneously, suggesting that LRS may occur in some of the remaining (62.6%) genes. Moreover, 12.5% of the genes lack both R-3 and G+4, potentially leading to sLRS. Compared with 11 genes known to undergo LRS, 10 genes with experimental evidence for high fidelity A+1T+2G+3 initiation codons adhered much more strongly to the R-3/G+4 rule. Among the intron-less histone genes, only the H3 genes adhere to the R-3/G+4 rule, while the H1, H2A, H2B and H4 genes usually lack either R-3 or G+4. To address in vivo the significance of the previously described LRS of H4 mRNAs, which results in alternative translation of the osteogenic growth peptide, transgenic mice were engineered that ubiquitously and constitutively express a mutant H4 mRNA with an A+1T+1 mutation. These transgenic mice, in particular the females, have a high bone mass phenotype, attributable to increased bone formation. These data suggest that many genes may fulfill cryptic functions by LRS.
authors.affiliation: Department of Orthopaedic Surgery, University of Southern California Los Angeles, CA 90033, USA.
authors.forename: Elisheva
authors.initials: E
authors.lastname: Smith
authors.forename: Todd E
authors.initials: TE
authors.lastname: Meyerrose
authors.forename: Thomas
authors.initials: T
authors.lastname: Kohler
authors.forename: Malka
authors.initials: M
authors.lastname: Namdar-Attar
authors.forename: Natti
authors.initials: N
authors.lastname: Bab
authors.forename: Olga
authors.initials: O
authors.lastname: Lahat
authors.forename: Tommy
authors.initials: T
authors.lastname: Noh
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.forename: Mazen W
authors.initials: MW
authors.lastname: Karaman
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Hacia
authors.forename: Ting T
authors.initials: TT
authors.lastname: Chen
authors.forename: Jan A
authors.initials: JA
authors.lastname: Nolta
authors.forename: Ralph
authors.initials: R
authors.lastname: Müller
authors.forename: Itai
authors.initials: I
authors.lastname: Bab
authors.forename: Baruch
authors.initials: B
authors.lastname: Frenkel
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000000981:diagnostic imaging; D018387:Codon, Initiator; D005260:Female; D016678:Genome; D006657:Histones / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009711:Nucleotides / Q000032:analysis; D010012:Osteogenesis; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000737:chemistry; D011859:Radiography; D012270:Ribosomes / Q000502:physiology*
chemical_list: D018387:Codon, Initiator; D006657:Histones; D009711:Nucleotides; D012333:RNA, Messenger
references.citation: Br J Haematol. 2003 Apr;121(1):76-85
references.pmid: 12670334
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3775-81
references.pmid: 12824416
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9416-21
references.pmid: 12872002
references.citation: J Biol Chem. 2003 Oct 31;278(44):43178-87
references.pmid: 12937168
references.citation: J Biol Chem. 2004 Feb 27;279(9):7685-91
references.pmid: 14670976
references.citation: Mol Cell. 2004 Apr 23;14(2):183-93
references.pmid: 15099518
references.citation: Genome Res. 2004 Jun;14(6):1188-90
references.pmid: 15173120
references.citation: Bone. 2004 Jul;35(1):65-73
references.pmid: 15207742
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W449-56
references.pmid: 15215428
references.citation: Cell. 1986 Jan 31;44(2):283-92
references.pmid: 3943125
references.citation: J Mol Biol. 1986 Apr 5;188(3):415-31
references.pmid: 3525846
references.citation: J Bone Miner Res. 1987 Dec;2(6):595-610
references.pmid: 3455637
references.citation: Gene. 1999 Oct 18;239(1):1-14
references.pmid: 10571029
references.citation: Cell. 2000 Jan 21;100(2):197-207
references.pmid: 10660043
references.citation: J Orthop Res. 2000 Jan;18(1):133-9
references.pmid: 10716289
references.citation: FEBS Lett. 2000 Mar 31;470(3):263-8
references.pmid: 10745079
references.citation: Nat Genet. 2000 May;25(1):25-9
references.pmid: 10802651
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9437-42
references.pmid: 10931945
references.citation: J Biol Chem. 2000 Oct 20;275(42):32747-52
references.pmid: 10921914
references.citation: Genomics. 2001 Jan 15;71(2):142-9
references.pmid: 11161807
references.citation: Nature. 2001 Feb 15;409(6822):860-921
references.pmid: 11237011
references.citation: Mol Endocrinol. 2001 Jul;15(7):1093-103
references.pmid: 11435610
references.citation: Genes Dev. 2001 Jul 1;15(13):1593-612
references.pmid: 11445534
references.citation: Science. 2001 Aug 10;293(5532):1074-80
references.pmid: 11498575
references.citation: J Biol Chem. 2001 Nov 9;276(45):41543-6
references.pmid: 11562357
references.citation: Cell. 2001 Nov 16;107(4):513-23
references.pmid: 11719191
references.citation: Exp Eye Res. 2001 Dec;73(6):827-36
references.pmid: 11846513
references.citation: Mol Cell Biol. 2002 Apr;22(8):2586-97
references.pmid: 11909953
references.citation: Leuk Res. 2002 Sep;26(9):839-48
references.pmid: 12127560
references.citation: Biopolymers. 2002;66(1):33-48
references.pmid: 12228919
references.citation: Genomics. 2002 Nov;80(5):487-98
references.pmid: 12408966
references.citation: Gene. 2002 Oct 16;299(1-2):1-34
references.pmid: 12459250
references.citation: J Pept Res. 2002 Dec;60(6):336-47
references.pmid: 12464112
references.citation: Nature. 2002 Dec 5;420(6915):520-62
references.pmid: 12466850
references.citation: J Biol Chem. 2003 Feb 7;278(6):3536-44
references.pmid: 12435745
references.citation: Nucleic Acids Res. 1989 Jan 25;17(2):795
references.pmid: 2915930
references.citation: Biochim Biophys Acta. 1989 Mar 1;1007(2):140-50
references.pmid: 2920170
references.citation: Nucleic Acids Res. 1990 Oct 25;18(20):6097-100
references.pmid: 2172928
references.citation: Mol Cell Biol. 1991 Nov;11(11):5541-50
references.pmid: 1922062
references.citation: J Cell Biol. 1991 Nov;115(4):887-903
references.pmid: 1955461
references.citation: EMBO J. 1992 May;11(5):1867-73
references.pmid: 1582415
references.citation: Bone. 1993 Mar-Apr;14(2):173-82
references.pmid: 8334036
references.citation: J Biol Chem. 1995 Apr 28;270(17):10236-45
references.pmid: 7730328
references.citation: Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11598-602
references.pmid: 8524811
references.citation: Blood. 1996 Dec 15;88(12):4719-24
references.pmid: 8977266
references.citation: Development. 1996 Dec;122(12):4131-8
references.pmid: 9012532
references.citation: Mol Cell Biol. 1997 May;17(5):2475-84
references.pmid: 9111316
references.citation: Endocrinology. 1997 May;138(5):2109-16
references.pmid: 9112411
references.citation: EMBO J. 1997 May 1;16(9):2482-92
references.pmid: 9171361
references.citation: Clin Orthop Relat Res. 1997 Jul;(340):267-75
references.pmid: 9224265
references.citation: Stud Health Technol Inform. 1997;40:61-79
references.pmid: 10168883
references.citation: Bone. 1998 Mar;22(3):189-94
references.pmid: 9514210
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8817-22
references.pmid: 9671762
references.citation: Cell Biol Int. 1998;22(4):313-9
references.pmid: 10101048
references.citation: J Biol Chem. 1999 May 14;274(20):14474-81
references.pmid: 10318873
references.citation: J Bone Miner Res. 1999 Jul;14(7):1167-74
references.pmid: 10404017
references.citation: Adv Enzyme Regul. 1999;39:263-73
references.pmid: 10470377