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Inosine RNA modifications are enriched at the codon wobble position in mouse oocytes and eggs†.

ABSTRACT: Mammalian oocytes and eggs are transcriptionally quiescent and depend on post-transcriptional mechanisms for proper maturation. Post-transcriptional mRNA modifications comprise an important regulatory mechanism that can alter protein and miRNA recognition sites, splicing, stability, secondary structure, and protein coding. We discovered that fully grown mouse germinal vesicle oocytes and metaphase II eggs display abundant inosine mRNA modifications compared to growing oocytes from postnatal day 12 oocytes. These inosines were enriched in mRNA protein coding regions (CDS) and specifically located at the third codon base, or wobble position. Inosines, observed at lower frequencies in CDS of somatic tissues, were similarly enriched at the codon wobble position. In oocytes and eggs, inosine modifications lead primarily to synonymous changes in mRNA transcripts. Inosines may ultimately affect maternal mRNA stability by changing codon usage, thereby altering translational efficiency and translationally coupled mRNA degradation. These important observations advance our understanding of post-transcriptional mechanisms contributing to mammalian oocyte maturation.

SUBMITTER: Brachova P

PROVIDER: S-EPMC6877758 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Inosine RNA modifications are enriched at the codon wobble position in mouse oocytes and eggs†.

Brachova Pavla P Alvarez Nehemiah S NS Hong Xiaoman X Gunewardena Sumedha S Vincent Kailey A KA Latham Keith E KE Christenson Lane K LK

Biology of reproduction 20191101 5

Mammalian oocytes and eggs are transcriptionally quiescent and depend on post-transcriptional mechanisms for proper maturation. Post-transcriptional mRNA modifications comprise an important regulatory mechanism that can alter protein and miRNA recognition sites, splicing, stability, secondary structure, and protein coding. We discovered that fully grown mouse germinal vesicle oocytes and metaphase II eggs display abundant inosine mRNA modifications compared to growing oocytes from postnatal day ...[more]

PMID: 31346607

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Project description:Human tRNA(Lys3)(UUU) (htRNA(Lys3)(UUU)) decodes the lysine codons AAA and AAG during translation and also plays a crucial role as the primer for HIV-1 (human immunodeficiency virus type 1) reverse transcription. The posttranscriptional modifications 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U(34)), 2-methylthio-N(6)-threonylcarbamoyladenosine (ms(2)t(6)A(37)), and pseudouridine (?(39)) in the tRNA's anticodon domain are critical for ribosomal binding and HIV-1 reverse transcription. To understand the importance of modified nucleoside contributions, we determined the structure and function of this tRNA's anticodon stem and loop (ASL) domain with these modifications at positions 34, 37, and 39, respectively (hASL(Lys3)(UUU)-mcm(5)s(2)U(34);ms(2)t(6)A(37);?(39)). Ribosome binding assays in vitro revealed that the hASL(Lys3)(UUU)-mcm(5)s(2)U(34);ms(2)t(6)A(37);?(39) bound AAA and AAG codons, whereas binding of the unmodified ASL(Lys3)(UUU) was barely detectable. The UV hyperchromicity, the circular dichroism, and the structural analyses indicated that ?(39) enhanced the thermodynamic stability of the ASL through base stacking while ms(2)t(6)A(37) restrained the anticodon to adopt an open loop conformation that is required for ribosomal binding. The NMR-restrained molecular-dynamics-derived solution structure revealed that the modifications provided an open, ordered loop for codon binding. The crystal structures of the hASL(Lys3)(UUU)-mcm(5)s(2)U(34);ms(2)t(6)A(37);?(39) bound to the 30S ribosomal subunit with each codon in the A site showed that the modified nucleotides mcm(5)s(2)U(34) and ms(2)t(6)A(37) participate in the stability of the anticodon-codon interaction. Importantly, the mcm(5)s(2)U(34)·G(3) wobble base pair is in the Watson-Crick geometry, requiring unusual hydrogen bonding to G in which mcm(5)s(2)U(34) must shift from the keto to the enol form. The results unambiguously demonstrate that modifications pre-structure the anticodon as a key prerequisite for efficient and accurate recognition of cognate and wobble codons.

Dataset Information

Inosine RNA modifications are enriched at the codon wobble position in mouse oocytes and eggs†.

Publications

Inosine RNA modifications are enriched at the codon wobble position in mouse oocytes and eggs†.

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