Distal nucleotides affect the rate of stop codon read-through

doi:10.15302/J-QB-022-0298

Quantitative Biology

2023, Vol. 11

Issue (1): 44-58 https://doi.org/10.15302/J-QB-022-0298

本期目录

Distal nucleotides affect the rate of stop codon read-through

Luciana I. Escobar¹, Andres M. Alonso², Jorge R. Ronderos³, Luis Diambra¹(

)

¹. CREG, Universidad Nacional de La Plata-CONICET, La Plata CP 1900, Argentina
². INTech, Universidad Nacional de San Martin, Chascomus CP 7130, Argentina
³. FCNyM, Universidad Nacional de La Plata, La Plata CP 1900, Argentina

全文: PDF(5942 KB) HTML

Abstract：

Background: A key step in gene expression is the recognition of the stop codon to terminate translation at the correct position. However, it has been observed that ribosomes can misinterpret the stop codon and continue the translation in the 3′UTR region. This phenomenon is called stop codon read-through (SCR). It has been suggested that these events would occur on a programmed basis, but the underlying mechanisms are still not well understood.

Methods: Here, we present a strategy for the comprehensive identification of SCR events in the Drosophila melanogaster transcriptome by evaluating the ribosomal density profiles. The associated ribosomal leak rate was estimated for every event identified. A statistical characterization of the frequency of nucleotide use in the proximal region to the stop codon in the sequences associated to SCR events was performed.

Results: The results show that the nucleotide usage pattern in transcripts with the UGA codon is different from the pattern for those transcripts ending in the UAA codon, suggesting the existence of at least two mechanisms that could alter the translational termination process. Furthermore, a linear regression models for each of the three stop codons was developed, and we show that the models using the nucleotides at informative positions outperforms those models that consider the entire sequence context to the stop codon.

Conclusions: We report that distal nucleotides can affect the SCR rate in a stop-codon dependent manner.

Key words： translational readthrough stop codons translational termination ribosomal density profiles nucleotide usage frequency

收稿日期: 2021-05-06 出版日期: 2023-03-13

Corresponding Author(s): Luis Diambra

引用本文:

. [J]. Quantitative Biology, 2023, 11(1): 44-58.
Luciana I. Escobar, Andres M. Alonso, Jorge R. Ronderos, Luis Diambra. Distal nucleotides affect the rate of stop codon read-through. Quant. Biol., 2023, 11(1): 44-58.

链接本文:

https://academic.hep.com.cn/qb/CN/10.15302/J-QB-022-0298
https://academic.hep.com.cn/qb/CN/Y2023/V11/I1/44

Fig.1

Fig.2

Fig.3

Fig.4

Fig.5

Fig.6

Fig.7

Fig.8

1	A., Brown, S., Shao, J., Murray, R. S. Hegde, (2015). Structural basis for stop codon recognition in eukaryotes. Nature, 524: 493–496 https://doi.org/10.1038/nature14896
2	M., Ryoji, K. Hsia, (1983). Read-through translation. Trends Biochem. Sci., 8: 88–90 https://doi.org/10.1016/0968-0004(83)90256-6
3	D. N. Robinson, (1997). Examination of the function of two kelch proteins generated by stop codon suppression. Development, 124: 1405–1417 https://doi.org/10.1242/dev.124.7.1405
4	I., Jungreis, M. F., Lin, R., Spokony, C. S., Chan, N., Negre, A., Victorsen, K. P. White, (2011). Evidence of abundant stop codon readthrough in Drosophila and other metazoa. Genome Res., 21: 2096–2113 https://doi.org/10.1101/gr.119974.110
5	J., Freitag, J. Ast, (2012). Cryptic peroxisomal targeting via alternative splicing and stop codon read-through in fungi. Nature, 485: 522–525 https://doi.org/10.1038/nature11051
6	G., Loughran, I., Jungreis, I., Tzani, M., Power, R. I., Dmitriev, I. P., Ivanov, M. Kellis, J. Atkins, (2018). Stop codon readthrough generates a C-terminally extended variant of the human vitamin D receptor with reduced calcitriol response. J. Biol. Chem., 293: 4434–4444 https://doi.org/10.1074/jbc.M117.818526
7	T. von der Haar, M. Tuite, (2007). Regulated translational bypass of stop codons in yeast. Trends Microbiol., 15: 78–86 https://doi.org/10.1016/j.tim.2006.12.002
8	G., Loughran, M. Y., Chou, I. P., Ivanov, I., Jungreis, M., Kellis, A. M., Kiran, P. V. Baranov, J. Atkins, (2014). Evidence of efficient stop codon readthrough in four mammalian genes. Nucleic Acids Res., 42: 8928–8938 https://doi.org/10.1093/nar/gku608
9	S. Eswarappa, A. Potdar, W. Koch, Y., Fan, K., Vasu, D., Lindner, B., Willard, L. Graham, P. DiCorleto, P. Fox, (2014). Programmed translational readthrough generates antiangiogenic VEGF-Ax. Cell, 157: 1605–1618 https://doi.org/10.1016/j.cell.2014.04.033
10	F. Schueren, (2016). Functional translational readthrough: A systems biology perspective. PLoS Genet., 12: e1006196 https://doi.org/10.1371/journal.pgen.1006196
11	R. B., Weiss, D. M., Dunn, J. F. Atkins, R. Gesteland, (1990). Ribosomal frameshifting from ‒2 to +50 nucleotides. Prog. Nucleic Acid Res. Mol. Biol., 39: 159–183 https://doi.org/10.1016/S0079-6603(08)60626-1
12	N. M., Wills, M., Connor, C. C., Nelson, C. C., Rettberg, W. M., Huang, R. F. Gesteland, J. Atkins, (2008). Translational bypassing without peptidyl-tRNA anticodon scanning of coding gap mRNA. EMBO J., 27: 2533–2544 https://doi.org/10.1038/emboj.2008.170
13	H. Beier, (2001). Misreading of termination codons in eukaryotes by natural nonsense suppressor tRNAs. Nucleic Acids Res., 29: 4767–4782 https://doi.org/10.1093/nar/29.23.4767
14	A. E. Firth, (2012). Non-canonical translation in RNA viruses. J. Gen. Virol., 93: 1385–1409 https://doi.org/10.1099/vir.0.042499-0
15	P. Steneberg, (2001). A novel stop codon readthrough mechanism produces functional Headcase protein in Drosophila trachea. EMBO Rep., 2: 593–597 https://doi.org/10.1093/embo-reports/kve128
16	L., Harrell, U. Melcher, J. Atkins, (2002). Predominance of six different hexanucleotide recoding signals 3′ of read-through stop codons. Nucleic Acids Res., 30: 2011–2017 https://doi.org/10.1093/nar/30.9.2011
17	M., Dabrowski, Z. Bukowy-Bieryllo, (2015). Translational readthrough potential of natural termination codons in eucaryotes―The impact of RNA sequence. RNA Biol., 12: 950–958 https://doi.org/10.1080/15476286.2015.1068497
18	A. G., Cridge, C., Crowe-McAuliffe, S. F. Mathew, W. Tate, (2018). Eukaryotic translational termination efficiency is influenced by the 3′ nucleotides within the ribosomal mRNA channel. Nucleic Acids Res., 46: 1927–1944 https://doi.org/10.1093/nar/gkx1315
19	M., Dabrowski, Z. Bukowy-Bieryllo, (2018). Advances in therapeutic use of a drug-stimulated translational readthrough of premature termination codons. Mol. Med., 24: 25 https://doi.org/10.1186/s10020-018-0024-7
20	M. T., Howard, B. H., Shirts, L. M., Petros, K. M., Flanigan, R. F. Gesteland, J. Atkins, (2000). Sequence specificity of aminoglycoside-induced stop condon readthrough: potential implications for treatment of Duchenne muscular dystrophy. Ann. Neurol., 48: 164–169 https://doi.org/10.1002/1531-8249(200008)48:2<164::AID-ANA5>3.0.CO;2-B
21	L., Bidou, V., Allamand, J. Rousset, (2012). Sense from nonsense: therapies for premature stop codon diseases. Trends Mol. Med., 18: 679–688 https://doi.org/10.1016/j.molmed.2012.09.008
22	C., Floquet, I., Hatin, J. Rousset, (2012). Statistical analysis of readthrough levels for nonsense mutations in mammalian cells reveals a major determinant of response to gentamicin. PLoS Genet., 8: e1002608 https://doi.org/10.1371/journal.pgen.1002608
23	K. M., Keeling, X., Xue, G. Gunn, D. Bedwell, (2014). Therapeutics based on stop codon readthrough. Annu. Rev. Genomics Hum. Genet., 15: 371–394 https://doi.org/10.1146/annurev-genom-091212-153527
24	A. M. Weiner, (1971). Natural read-through at the UGA termination signal of Q-beta coat protein cistron. Nat. New Biol., 234: 206–209 https://doi.org/10.1038/newbio234206a0
25	H. Pelham, (1978). Leaky UAG termination codon in tobacco mosaic virus RNA. Nature, 272: 469–471 https://doi.org/10.1038/272469a0
26	C. M., Brown, S. P. Dinesh-Kumar, W. Miller, (1996). Local and distant sequences are required for efficient readthrough of the barley yellow dwarf virus PAV coat protein gene stop codon. J. Virol., 70: 5884–5892 https://doi.org/10.1128/jvi.70.9.5884-5892.1996
27	O., Namy, G. Duchateau-Nguyen, J. Rousset, (2002). Translational readthrough of the PDE2 stop codon modulates cAMP levels in Saccharomyces cerevisiae. Mol. Microbiol., 43: 641–652 https://doi.org/10.1046/j.1365-2958.2002.02770.x
28	H. S., Chittum, W. S., Lane, B. A., Carlson, P. P., Roller, F. D., Lung, B. J. Lee, D. Hatfield, (1998). Rabbit beta-globin is extended beyond its UGA stop codon by multiple suppressions and translational reading gaps. Biochemistry, 37: 10866–10870 https://doi.org/10.1021/bi981042r
29	B. R., Klagges, G., Heimbeck, T. A., Godenschwege, A., Hofbauer, G. O., Pflugfelder, R., Reifegerste, D., Reisch, M., Schaupp, S. Buchner, (1996). Invertebrate synapsins: a single gene codes for several isoforms in Drosophila. J. Neurosci., 16: 3154–3165 https://doi.org/10.1523/JNEUROSCI.16-10-03154.1996
30	M. F., Lin, I. Jungreis, (2011). PhyloCSF: a comparative genomics method to distinguish protein coding and non-coding regions. Bioinformatics, 27: i275–i282 https://doi.org/10.1093/bioinformatics/btr209
31	I., Jungreis, C. S., Chan, R. M., Waterhouse, G., Fields, M. F. Lin, (2016). Evolutionary dynamics of abundant stop codon readthrough. Mol. Biol. Evol., 33: 3108–3132 https://doi.org/10.1093/molbev/msw189
32	J. G., Dunn, C. K., Foo, N. G., Belletier, E. R. Gavis, J. Weissman, (2013). Ribosome profiling reveals pervasive and regulated stop codon readthrough in Drosophila melanogaster. eLife, 2: e01179 https://doi.org/10.7554/eLife.01179
33	F., Schueren, T., Lingner, R., George, J., Hofhuis, C., Dickel, J. rtner, (2014). Peroxisomal lactate dehydrogenase is generated by translational readthrough in mammals. eLife, 3: e03640 https://doi.org/10.7554/eLife.03640
34	N. T., Ingolia, S., Ghaemmaghami, J. R. S. Newman, J. Weissman, (2009). Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science, 324: 218–223 https://doi.org/10.1126/science.1168978
35	A. C., Stiebler, J., Freitag, K. O., Schink, T., Stehlik, B. A., Tillmann, J. Ast, (2014). Ribosomal readthrough at a short UGA stop codon context triggers dual localization of metabolic enzymes in fungi and animals. PLoS Genet., 10: e1004685 https://doi.org/10.1371/journal.pgen.1004685
36	L. S., Gramates, S. J., Marygold, G. D., Santos, J. M., Urbano, G., Antonazzo, B. B., Matthews, A. J., Rey, C. J., Tabone, M. A., Crosby, D. B. Emmert, et al.. (2017). FlyBase at 25: looking to the future. Nucleic Acids Res., 45: D663–D671 https://doi.org/10.1093/nar/gkw1016
37	A., Singh, L. E., Manjunath, P., Kundu, S., Sahoo, A., Das, H. R., Suma, P. L. Fox, S. Eswarappa, (2019). Let-7a-regulated translational readthrough of mammalian AGO1 generates a microRNA pathway inhibitor. EMBO J., 38: e100727 https://doi.org/10.15252/embj.2018100727
38	L. Diambra, (2017). Differential bicodon usage in lowly and highly abundant proteins. PeerJ, 5: e3081 https://doi.org/10.7717/peerj.3081
39	A. Dana, (2012). Determinants of translation elongation speed and ribosomal profiling biases in mouse embryonic stem cells. PLOS Comput. Biol., 8: e1002755 https://doi.org/10.1371/journal.pcbi.1002755
40	C., McCarthy, A. Carrea, (2017). Bicodon bias can determine the role of synonymous SNPs in human diseases. BMC Genomics, 18: 227 https://doi.org/10.1186/s12864-017-3609-6
41	A. K., Sharma, P., Sormanni, N., Ahmed, P., Ciryam, U. A., Friedrich, G. Kramer, E. Brien, (2019). A chemical kinetic basis for measuring translation initiation and elongation rates from ribosome profiling data. PLOS Comput. Biol., 15: e1007070 https://doi.org/10.1371/journal.pcbi.1007070
42	T., Tuller, A., Carmi, K., Vestsigian, S., Navon, Y., Dorfan, J., Zaborske, T., Pan, O., Dahan, I. Furman, (2010). An evolutionarily conserved mechanism for controlling the efficiency of protein translation. Cell, 141: 344–354 https://doi.org/10.1016/j.cell.2010.03.031
43	A. E., Firth, N. M., Wills, R. F. Gesteland, J. Atkins, (2011). Stimulation of stop codon readthrough: frequent presence of an extended 3' RNA structural element. Nucleic Acids Research, 39: 6679–6691 https://doi.org/10.1093/nar/gkr224
44	S., Blanchet, D., Cornu, M. Argentini, (2014). New insights into the incorporation of natural suppressor tRNAs at stop codons in Saccharomyces cerevisiae. Nucleic Acids Res., 42: 10061–10072 https://doi.org/10.1093/nar/gku663
45	M. Martin, (2011). Cutadapt removes adapter sequences from highthroughput sequencing reads. EMBnet. J., 17: 10 https://doi.org/10.14806/ej.17.1.200
46	B. Langmead, S. Salzberg, (2012). Fast gapped-read alignment with Bowtie 2. Nat. Methods, 9: 357–359 https://doi.org/10.1038/nmeth.1923
47	C., Trapnell, L. Pachter, S. Salzberg, (2009). TopHat: discovering splice junctions with RNA-Seq. Bioinformatics, 25: 1105–1111 https://doi.org/10.1093/bioinformatics/btp120
48	H., Li, B., Handsaker, A., Wysoker, T., Fennell, J., Ruan, N., Homer, G., Marth, G. Abecasis, R. Durbin, (2009). The sequence alignment/map format and SAMtools. Bioinformatics, 25: 2078–2079 https://doi.org/10.1093/bioinformatics/btp352
49	D. J. MacKayD. Mac Kay. (2003) Information Theory, Inference and Learning Algorithms. Cambridge: Cambridge University Press

[1]	Supplementary materials	Download
[2]	Table_S1	Download
[3]	Table_S2	Download

Viewed

Full text

Abstract

Cited

Shared

Discussed