Determinants of genome-wide distribution and evolution of uORFs in eukaryotes

Zhang, Hong; Wang, Yirong; Wu, Xinkai; Tang, Xiaolu; Wu, Changcheng; Lü, Jian

doi:10.1038/s41467-021-21394-y

Cited by 54 publications

(49 citation statements)

References 164 publications

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“…Authors found that human uORFs were not under selection to maintain amino acid identity, but uORF start codons were conserved and under strong selective pressure. The recently published Zhang et al (2021) investigation of uORFs evolution in eukaryotes also confirms this observation.…”

Section: Discussionsupporting

confidence: 57%

Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

et al. 2021

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Congenital aniridia (AN) is a severe autosomal dominant panocular disorder associated with pathogenic variants in the PAX6 gene. Previously, we performed a molecular genetic study of a large cohort of Russian patients with AN and revealed four noncoding nucleotide variants in the PAX6 5ʹUTR. 14 additional PAX6-5ʹUTR variants were also reported in the literature, but the mechanism of their pathogenicity remained unclear. In the present study, we experimentally analyze five patient-derived PAX6 5ʹUTR-variants: four variants that we identified in Russian patients (c.-128-2delA, c.-125dupG, c.-122dupG, c.-118_-117del) and one previously reported (c.-52+5G>C). We show that the variants lead to a decrease in the protein translation efficiency, while mRNA expression level is not significantly reduced. Two of these variants also affect splicing. Furthermore, we predict and experimentally validate the presence of an evolutionarily conserved small uORF in the PAX6 5ʹUTR.All studied variants lead to the frameshift of the uORF, resulting in its extension.This extended out-of-frame uORF overlaps with the downstream CDS and thereby reduces its translation efficiency. We conclude that the uORF frameshift may be the main mechanism of pathogenicity for at least 15 out of 18 known PAX6 5ʹUTR variants. Moreover, we predict additional uORFs in the PAX6 5ʹUTR.

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Section: Discussionsupporting

confidence: 57%

Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

et al. 2021

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“…Upstream open reading frames (uORFs) are common translational repressors that act in cis of eukaryotic protein-coding transcripts. Considering AUG as a translation start, 30-70% of genes contain at least one potential uORF in moss, Arabidopsis, fly, mouse and human [1][2][3] . According to the scanning model of mRNA translation, the 43S preinitiation complex binds the 5' cap and scans the 5' untranslated region (UTR) to search for an optimal initiation sequence [4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

Arabidopsis uORF-containing mRNAs behave differently from NMD targets

Hsu

2021

Preprint

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Upstream ORFs (uORFs) are widespread cis-regulatory elements in the 5 prime untranslated regions of eukaryotic genes. Translation of uORFs could negatively regulate protein synthesis by repressing main ORF (mORF) translation and by reducing mRNA stability presumably through nonsense-mediated decay (NMD). While the above expectations were supported in animals, they have not been extensively tested in plants. Using ribosome profiling, we systematically identified 2093 Actively Translated uORFs (ATuORFs) in Arabidopsis seedlings and examined their roles in gene expression regulation by integrating multiple genome-wide datasets. Compared with genes without uORFs, we found ATuORFs result in 38%, 14%, and 43% reductions in translation efficiency, mRNA stability, and protein levels, respectively. The effects of predicted but not actively translated uORFs are much weaker than those of ATuORFs. Interestingly, ATuORF-containing genes are also expressed at higher levels and encode longer proteins with conserved domains, features that are common in evolutionarily older genes. Moreover, we provide evidence that uORF translation in plants, unlike in vertebrates, generally does not trigger NMD. We found ATuORF-containing transcripts are degraded through 5 prime to 3 prime decay, while NMD targets are degraded through both 5 prime to 3 prime and 3 prime to 5 prime decay, suggesting uORF-associated mRNA decay and NMD have distinct genetic requirements. Furthermore, we showed ATuORFs and NMD repress translation through separate mechanisms. Our results reveal that the potent inhibition of uORFs on mORF translation and mRNA stability in plants are independent of NMD, highlighting a fundamental difference in gene expression regulation by uORFs in the plant and animal kingdoms.

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“…In addition to the transcriptional control, accumulating evidence supports a prominent contribution of translational regulation in gene expression especially in eukaryotes. Microproteins encoded by uORFs have been found to pose a critical role in the mRNA translation process (Zhang et al, 2021). In the human genome, about 35% of genes contain uORFs.…”

Section: Microproteins Function At the Translational Levelmentioning

confidence: 99%

Microproteins: from behind the scenes to the spotlight

Jiang

Lou

Hou

2021

GENOME INSTAB. DIS.

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Microproteins, less than 200 amino acids, have been usually regarded as non-functional for a long time. We do not recognize this "dark matter" in the proteome until developing new bioinformatic, biochemical and proteomic techniques. The fast-growing number of the identified microproteins and their emerging roles in various biological processes begin to attract more and more attention. Here, we summarize the recent progress in this field mainly from four aspects: (1) brief history and various definitions of microproteins; (2) three main strategies to identify microproteins; (3) multiple regulatory mechanisms of microproteins; (4) biological functions of microproteins, with a particular focus on genome stability maintenance and their relevance to human diseases. Finally, we discuss some open questions and therapeutic opportunities hiding in these small newcomers. Keywords Microproteins • Small open reading frames • Genome stability • DNA repair • DNA replication • Cancer Abbreviations aa Amino acids alt-ORFs Alternative-ORFs bHLH Basic helix-loop-helix CASIMO1 Cancer-associated small integral membrane open reading frame 1 circRNA Circular RNA cNHEJ Canonical non-homologous end joining CYREN Cell cycle regulator of NHEJ dNDPs Deoxynucleotide diphosphates dNTPs Deoxynucleotide triphosphates DTL Denticleless DSB DNA double-strand break DYNLL1 Dynein light chain LC8-type 1 EPHX1 Epoxide hydrolase 1 ER Endoplasmic reticulum ERLIC Electrostatic repulsion hydrophilic interaction chromatography EST Expressed sequence tags FBXW7 F-box and WD repeat domain containing 7 HR Homologous recombination

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Determinants of genome-wide distribution and evolution of uORFs in eukaryotes

Cited by 54 publications

References 164 publications

Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

Arabidopsis uORF-containing mRNAs behave differently from NMD targets

Microproteins: from behind the scenes to the spotlight

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