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Nonsense but Not Missense Mutations Can Decrease the Abundance Of MOLECULAR AND CELLULAR BIOLOGY, Sept. 1994, p. 6326-6336 Vol. 14, No. 9 0270-7306/94/$04.00+0 Copyright © 1994, American Society for Microbiology Nonsense but Not Missense Mutations Can Decrease the Abundance of Nuclear mRNA for the Mouse Major Urinary Protein, While Both Types of Mutations Can Facilitate Exon Skipping PHILLIP BELGRADERt AND LYNNE E. MAQUAT* Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263 Received 28 April 1994/Returned for modification 13 June 1994/Accepted 22 June 1994 In an effort to understand the mechanisms by which nonsense codons affect RNA metabolism in mammalian cells, nonsense mutations were generated within the gene for the secretory major urinary protein (MUP) of mice. The translation of MUP mRNA normally begins within exon 1 and terminates within exon 6, the penultimate exon. Through the use of Northern (RNA) blot hybridization and assays that couple reverse transcription and PCR, a nonsense mutation within codon 50 of exon 2 or codon 143 of exon 5 was found to reduce the abundance of fully spliced, nuclear MUP mRNA to 10 to 201% of normal without an additional reduction in the abundance of cytoplasmic mRNA. In contrast, a nonsense mutation within codon 172 of exon 5 was found to have no effect on the abundance of MUP mRNA. These findings suggest that a boundary between nonsense mutations that do and do not reduce the abundance of nuclear mRNA exists within the exon preceding the exon that harbors the normal site of translation termination. In this way, the boundary is analogous to the boundary that exists within the penultimate exon of the human gene for the cytosolic enzyme triosephosphate isomerase. Assays for exon skipping, i.e., the removal of an exon as a part of the flanking introns during the process of splicing, reveal that 0.1, 2.0, and 0.1% of MUP mRNA normally lack exon 5, exon 6, and exons 5 plus 6, respectively. Relative to normal, the two nonsense mutations within exon 5 increase the abundance of RNA lacking exon 5 on average 20-fold and increase the abundance ofRNA lacking exons 5 plus 6 on average 5-fold. Since only one ofthese nonsense mutations also reduces the abundance of fully spliced nuclear mRNA to 10 to 20%o of normal, the two mechanisms by which a nonsense mutation can alter nuclear RNA metabolism must be distinct. The analysis ofmissense mutations within codons 143 and 172, some ofwhich retain the nonsense mutation, indicates that the reduction in the abundance of fully spliced nuclear mRNA is dependent upon the premature termination of MUP mRNA translation, whereas skipping is attributable to nonsense mutation-mediated changes in exon 5 structure rather than to the premature termination of translation. The increase in exon 5 skipping by either the nonsense or missense mutations within codon 172 correlates with a decrease in the complementarity of exon 5 to Ul snRNA. This suggests that a 5' splice site may extend as far as 12 nucleotides into the upstream exon, which is, to our knowledge, the largest extension. In eukaryotes, protein-encoding genes that harbor a non- but not actually proven to be in the cytoplasm) is elicited by sense codon because of a nonsense or frameshift mutation nonsense codons within the first two-thirds of the coding often produce RNA that is metabolized abnormally. For some region, which preclude the translation of a stabilizing element genes, the product mRNA is increased in abundance because and activate what are thought to be multiple downstream the premature termination of translation precludes ribosome destabilizing elements (50). Decay is also dependent on the translocation either across a specific sequence in the coding products of the UPF1 and UPF3 genes (31, 32, 50, 51). The region, as exemplified by the c-fos, c-myc, and MA Tot] mRNAs decay of gag mRNA is elicited by nonsense codons residing (22, 49, 57, 58, 69), or sufficiently close to a higher-order more than approximately 10 codons upstream of the natural structure in the 3' untranslated region, as exemplified by termination codon, which presumably preclude ribosomal pro- specific histone mRNAs (8, 21, 34). The increase in mRNA gression sufficiently close to a higher-order structure residing abundance is invariably the result of an increase in the half-life 100 to 200 nucleotides (nt) downstream of the termination of cytoplasmic mRNA. For other genes, the product mRNA is codon (2, 3). In other cases, the decrease in mRNA abundance decreased in abundance by mechanisms that are just beginning by a nonsense codon is attributable to abnormal nuclear RNA to be unraveled (2-5, 17, 19, 27, 31, 37, 38, 42, 50, 54, 59, 66). metabolism. mRNAs that manifest this type of mechanism In some cases, the decrease in mRNA abundance is attribut- include hamster dihydrofolate reductase mRNA (29, 66), able to a decrease in the half-life of cytoplasmic mRNA (2, 3, human P-globin mRNA when it is produced from a simian 19, 37, 50, 58). This type of mechanism is probably best virus 40-based expression vector that has been integrated into understood for phosphoglycerate kinase 1 (PGKJ) mRNA of the genome of the Syrian hamster AF8 cell line (4), human Saccharomyces cerevisiae and gag mRNA of Rous sarcoma virus (RSV). The decay of PGKI mRNA (which is presumably triosephosphate isomerase (TPI) mRNA (6, 13), mouse T-cell receptor P mRNA (54), src mRNA of RSV (59), and the R2 RNA of minute virus of mice (MVM) (42). * It remains to be elucidated how a nonsense codon, which is Corresponding author. Mailing address: Roswell Park Cancer known to be mRNA translation in the Institute, Department of Human Genetics, Elm and Carlton Sts., recognized only during Buffalo, NY 14263. Phone: (716) 845-3325. Fax: (716) 845-8449. cytoplasm, can affect the abundance of nuclear mRNA. Possi- Electronic mail address: [email protected]. bly, different mechanisms pertain to different mRNAs. For t Present address: Armed Forces Institute of Pathology, Washing- example, a nonsense codon within the first three-fourths of the ton, DC 20306. translated portion of TPI mRNA decreases the abundance of 6326 VOL. 14, 1994 EFFECTS OF MUTATIONS ON NUCLEAR RNA 6327 fully-spliced, nuclear TPI mRNA by a mechanism that involves normal termination codon. In each of these aspects, nonsense tRNA and ribosomes (6). Neither the rate of TPI gene codons affect MUP and TPI RNA metabolism similarly (12, transcription initiation nor the level of any of the six introns in 13). However, while none of the nonsense mutations within TPI pre-mRNA is affected by a nonsense codon (13). In TPI mRNA alters the exon composition of the mRNA, each contrast, a nonsense codon within the MVM R2 mRNA or the nonsense mutation within exon 5 of MUP mRNA facilitates T-cell receptor f3 mRNA has been associated with the accu- exon 5 skipping. Given that only a subset of the nonsense mulation of the respective intron-containing pre-mRNA (42, codons that facilitate exon skipping reduce mRNA abundance, 54). Finally, a nonsense codon within the mRNAs for human exon 5 skipping must be independent of the mechanism by fibrillin (17), ornithine 8-aminotransferase (OAT) (17), Fan- which a nonsense mutation reduces mRNA abundance. Since coni anemia group C (20), factor VIII (44), or a-L-iduronidase missense mutations within exon 5 also facilitate exon 5 skip- (1), to name a few, has been associated with the generation of ping but do not reduce mRNA abundance, exon 5 skipping mRNA lacking the exon that harbors the nonsense codon. must be independent of the premature termination of MUP Presumably the exon, which is normally a constitutively spliced mRNA translation, while the reduction in mRNA abundance exon, is removed (i.e., skipped) during the process of RNA must be dependent on the premature termination of MUP splicing as a part of the flanking introns. The findings that a mRNA translation. nonsense codon can be associated with either retarded splicing or exon skipping have been interpreted by some investigators MATERIALS AND METHODS to indicate that a nonsense codon can influence either the choice or the efficiency of splice site utilization and that it may Plasmid constructions. pCMV_MUP5OTer was generated by thus be recognized in the context of the translational reading inserting 4 bp at the EcoRI site of the MUP 25D4 gene in frame in the nucleus. In support of this idea, none of the pCMV-MUP orm (referred to as pIE-MUP in reference 53) by nonsense mutations that appear to affect splice site utilization using Klenow fragment. Nonsense and missense codons within appears to be a part of either a 5' or a 3' splice site (although exon 5 were introduced into subclones of the 596-bp PvuII- for the Fanconi anemia group C mRNA only cDNA and not Kjpnl fragment of pCMV_MUPNorm with the mutagenic oligo- gene [i.e., intron] sequence information is available). Further- nucleotides 5' AATCTGGTTATCGGCCTG 3', 5' AATCT more, nonsense mutations appear to inhibit the splicing of the GGTACTCGGCCTG 3', 5' AATCTGGTT£iTCGGCCTG MVM R2 RNA only when they are in frame with the initiating 31, 5' AATCTGGT'ITICGGCCTG 3', and 5' TTACTGGCA AUG codon (42), and inhibitors of translation abrogate the TTUATAGGAC 3', in which the underlined nucleotides retarded splicing of T-cell receptor L pre-mRNA that has been deviate from the corresponding MUP gene sequence, and a attributed to the presence of a nonsense codon (54). Never- T7-Gen in vitro mutagenesis kit (U.S. Biochemical). The theless, none of the studies that associated a nonsense codon mutagenized fragments were used to construct pCMV- with a change in splicing addressed the effects of a comparably MuP143Ter, pcMv_MuP143Va1, pCMV-MUPI43GIn, pCMV- positioned missense codon, and there are numerous examples MUPl43LYs,and pCMV-MUPl72Ter, respectively.
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