The dark proteome: translation from noncanonical open reading frames

Wright, Bradley W.; Yi, Zixin; Weissman, Jonathan S.; Chen, Jin

doi:10.1016/j.tcb.2021.10.010

Cited by 109 publications

(81 citation statements)

References 127 publications

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“…Also, small peptides deriving from mitochondrial DNA (Humanin and MutS-C), called mitochondria-derived peptides (MDPs), have been described to have a protective role in cardiovascular diseases (Yang et al, 2019). Most of the characterized human SEPs and their physiological and functional roles have been reviewed recently (Wright et al, 2021).…”

Section: Implication Of Sorfs and Their Encoded Peptides In Humans: Relevant Examplesmentioning

confidence: 99%

Small Open Reading Frames, How to Find Them and Determine Their Function

et al. 2022

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Advances in genomics and molecular biology have revealed an abundance of small open reading frames (sORFs) across all types of transcripts. While these sORFs are often assumed to be non-functional, many have been implicated in physiological functions and a significant number of sORFs have been described in human diseases. Thus, sORFs may represent a hidden repository of functional elements that could serve as therapeutic targets. Unlike protein-coding genes, it is not necessarily the encoded peptide of an sORF that enacts its function, sometimes simply the act of translating an sORF might have a regulatory role. Indeed, the most studied sORFs are located in the 5′UTRs of coding transcripts and can have a regulatory impact on the translation of the downstream protein-coding sequence. However, sORFs have also been abundantly identified in non-coding RNAs including lncRNAs, circular RNAs and ribosomal RNAs suggesting that sORFs may be diverse in function. Of the many different experimental methods used to discover sORFs, the most commonly used are ribosome profiling and mass spectrometry. These can confirm interactions between transcripts and ribosomes and the production of a peptide, respectively. Extensions to ribosome profiling, which also capture scanning ribosomes, have further made it possible to see how sORFs impact the translation initiation of mRNAs. While high-throughput techniques have made the identification of sORFs less difficult, defining their function, if any, is typically more challenging. Together, the abundance and potential function of many of these sORFs argues for the necessity of including sORFs in gene annotations and systematically characterizing these to understand their potential functional roles. In this review, we will focus on the high-throughput methods used in the detection and characterization of sORFs and discuss techniques for validation and functional characterization.

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Section: Implication Of Sorfs and Their Encoded Peptides In Humans: Relevant Examplesmentioning

confidence: 99%

Small Open Reading Frames, How to Find Them and Determine Their Function

et al. 2022

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“…Over the last decade Ribo-seq has provided compelling evidence that the traditional rules of eukaryotic translation need to be revised. For example, translation initiation at near-cognate codons (CUG, GUG, UUG) is more widespread in mammalian genomes than previously thought (Wright et al, 2021). The analysis of Ribo-seq data has also been essential for the characterisation of a range of non-canonical ORFs, including N-terminal extensions (Ivanov et al, 2011), detecting translation of RNAs previously thought to be non-coding (Ji et al, 2015), and uncovering the regulatory role of ORFs initiating in the 5' leader sequence of mRNAs (i.e., upstream open reading frames) (Zhang et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Annotation of the non-canonical translatome reveals that CHO cell microproteins are a new class of mAb drug product impurity

Rivadeneyra

Tzani

Kelly

et al. 2022

Preprint

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Mass spectrometry (MS) has emerged as a powerful approach for the detection of Chinese hamster ovary (CHO) cell protein impurities in antibody drug products. The incomplete annotation of the Chinese hamster genome, however, limits the coverage of MS-based host cell protein (HCP) analysis. In this study, we performed ribosome footprint profiling (Ribo-seq) of translation initiation and elongation to refine the Chinese hamster genome annotation. Analysis of these data resulted in the identification of thousands of previously uncharacterised non-canonical proteoforms in CHO cells, such as N-terminally extended proteins and short open reading frames (sORFs) predicted to encode for microproteins. MS-based HCP analysis of adalimumab with the extended protein sequence database, resulted in the detection of CHO cell microprotein impurities in a mAb drug product for the first time. Further analysis revealed that the CHO cell microprotein population is altered over the course of cell culture and in response to a change in cell culture temperature. The annotation of non-canonical Chinese hamster proteoforms permits a more comprehensive characterisation of HCPs in antibody drug products using MS.

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“…Overlapping genes (OLGs) were first found in bacteriophages (Barrell, Air, and Hutchison 1976), and among biologists they are often assumed to be restricted to viruses. There are indeed many prominent examples in viruses beyond bacteriophages including in the pandemic viruses HIV and SARS-CoV-2 (Firth and Brierley 2012; Cassan et al 2016; Affram et al 2019; Nelson et al 2020; Firth 2020), but they have also recently been discovered in diverse cellular organisms, including bacteria (Kreitmeier et al 2022; Zehentner et al 2020b; Meydan, Vázquez-Laslop, and Mankin 2018), archaea (Gelsinger et al 2020), and mammals, including humans (Loughran et al 2020; Khan et al 2020; Mudge et al 2021; Cao et al 2021; Wright et al 2022). Research on OLGs within five years of their initial discovery investigated diverse topics including triple overlaps (Szekely 1978), information theory (Siegel and Fitch 1980; Smith and Waterman 1981; Yockey 1981), discussion of their evolution (Miyata and Yasunaga 1978; Yockey 1979), and the proposal that they may be widespread throughout life (Kolata 1977).…”

Section: Introductionmentioning

confidence: 99%

Why is the average collateral effect of synonymous mutations so similar across alternative reading frames?

Wichmann

Ardern

2022

Preprint

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The standard genetic code has been shown to have multiple interesting properties which impact on molecular biology and the evolutionary process. One facet of molecular biology where code structure is particularly important is the origin and evolution of overlapping genes. We have previously reported that the structure of the standard genetic code ensures that synonymous mutations in a protein coding gene will lead to a remarkably similar average "collateral" mutation effect size in at least four out of the five alternative reading frames. Here we show that only 0.26% of alternative codes with the block structure of the standard genetic code perform at least as well as the standard code in this property. Considering this finding within a code optimality framework suggests that this consistent effect size across the different frames may be adaptive. Here we give context for this finding and present a simple model where a trade-off between evolvability and robustness leads to an average mutation effect size which maximises population fitness. This supports the intuition that similar mutation effects across the different alternative reading frames may be an adaptive property of the standard genetic code which facilitates evolvability through the use of alternative reading frames.

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The dark proteome: translation from noncanonical open reading frames

Cited by 109 publications

References 127 publications

Small Open Reading Frames, How to Find Them and Determine Their Function

Small Open Reading Frames, How to Find Them and Determine Their Function

Annotation of the non-canonical translatome reveals that CHO cell microproteins are a new class of mAb drug product impurity

Why is the average collateral effect of synonymous mutations so similar across alternative reading frames?

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