Noncanonical open reading frames encode functional proteins essential for cancer cell survival

Prensner, John R.; Enache, Oana; Luria, Victor; Krug, Karsten; Clauser, Karl R.; Dempster, Joshua; Karger, Amir; Wang, Li; Stumbraite, Karolina; Wang, Vickie M.; Botta, Ginevra; Lyons, Nicholas; Goodale, Amy; Kalani, Zohra; Fritchman, Briana; Brown, Adam D.; Alan, Douglas; Green, Thomas; Yang, Xiaoping; Jaffe, Jacob D.; Roth, Jennifer A.; Piccioni, Federica; Kirschner, Marc W.; Ji, Zhe; Root, David E.; Golub, Todd R.

doi:10.1038/s41587-020-00806-2

Cited by 112 publications

(107 citation statements)

References 70 publications

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“…When an entire ORF is contained within an overlapping gene’s intron it is referred to as intron nesting 20 , 58 . True exon–exon overlaps make up the minority of transcript overlap in eukaryotes 8 , 23 but new technologies (Box 1 ) suggest that they may be more common than currently appreciated 11 , 12 .…”

Section: Overlapping Gene Topology and Functionmentioning

confidence: 99%

“…4c ) is one such example of a gene possessing two distinct and functional CDSs overlapping the same genomic sequence. These alternative ORFs 66 are often functionally related and implicated in a range of human diseases 12 , 67 . For example, the cyclin-dependent kinase inhibitor 2A (p16INK4a) and tumour suppressor ARF, which regulate the tumour suppressors retinoblastoma protein (RB) and p53 transcription factor 68 , are produced as alternatively spliced transcripts from what is now considered the same gene ( CDKN2A ), even though the proteins do not share sequence or structural similarity, and the E1b exon that produces the ARF protein is ~20 kb upstream of the other CDKN2A exons 68 .…”

Section: Overlapping Gene Topology and Functionmentioning

confidence: 99%

“…Overlapping ORFs discovered using the above methods have been verified using a variety of reverse genetics approaches, including CRISPR–Cas9 and catalytically dead Cas9 (dCas9) disruption 11 , 12 , 65 , as well as an attempt at proof-by-synthesis to establish the absence of any undiscovered overlapping genes 197 .…”

Section: Introductionmentioning

confidence: 99%

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Overlapping genes in natural and engineered genomes

2021

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Modern genome-scale methods that identify new genes, such as proteogenomics and ribosome profiling, have revealed, to the surprise of many, that overlap in genes, open reading frames and even coding sequences is widespread and functionally integrated into prokaryotic, eukaryotic and viral genomes. In parallel, the constraints that overlapping regions place on genome sequences and their evolution can be harnessed in bioengineering to build more robust synthetic strains and constructs. With a focus on overlapping protein-coding and RNA-coding genes, this Review examines their discovery, topology and biogenesis in the context of their genome biology. We highlight exciting new uses for sequence overlap to control translation, compress synthetic genetic constructs, and protect against mutation.

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Section: Overlapping Gene Topology and Functionmentioning

confidence: 99%

Section: Overlapping Gene Topology and Functionmentioning

confidence: 99%

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Overlapping genes in natural and engineered genomes

2021

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“…Microproteins have long been overlooked in genomic studies, mostly due to technical limitations linked to their small size 6 . But there is now increasing interest and investment towards identifying them and understanding their functions and possible roles in health and disease 7,8 . Well studied examples of functional human microproteins include NoBody 9 , PIGBOS 10 and Myoregulin 11 , while many more have been identified in other species such as mouse 12 , plants 13 , bacteria 14 and elsewhere 15 .…”

Section: Introductionmentioning

confidence: 99%

De novo birth of functional, human-specific microproteins

Vakirlis

Duggan

McLysaght

2021

Preprint

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We now have a growing understanding that functional short proteins can be translated out of small Open Reading Frames (sORF). Such ″microproteins″ can perform crucial biological tasks and can have considerable phenotypic consequences. However, their size makes them less amenable to genomic analysis, and their evolutionary origins and conservation are poorly understood. Given their short length it is plausible that some of these functional microproteins have recently originated entirely de novo from non-coding sequence. Here we test the possibility that de novo gene birth can produce microproteins that are functional ″out-of-the-box″. We reconstructed the evolutionary origins of human microproteins previously found to have measurable, statistically significant fitness effects. By tracing the appearance of each ORF and its transcriptional activation, we were able to show that, indeed, novel small proteins with significant phenotypic effects have emerged de novo throughout animal evolution, including many after the human-chimpanzee split. We show that traditional methods for assessing the coding potential of such sequences often fall short, due to the high variability present in the alignments and the absence of telltale evolutionary signatures that are not yet measurable. Thus we provide evidence that the functional potential intrinsic to sORFs can be rapidly, and frequently realised through de novo gene birth.

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“…Fewer alt-proteins have been characterized, including alt-FUS, which cooperates with FUS in formation of cytotoxic aggregates 7 , and alt-RPL36, which we have shown regulates the PI3K-AKT-mTOR pathway 8 . Recently, genome-scale CRISPR screens revealed that hundreds of smORFs regulate human cell growth and survival 9,10 . These studies demonstrate that defining the function of bioactive SEPs and alt-proteins represents a major opportunity to gain insights into biological complexity.…”

Section: Introductionmentioning

confidence: 99%

Nascent alt-protein chemoproteomics reveals a repressor of ribosome biogenesis

Cao

Harold

Bryant

et al. 2021

Preprint

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Ribosome biogenesis in eukaryotes is a highly regulated, essential cellular process. However, few repressors of ribosome biogenesis have been identified. Here, we identify and define the function of MINAS-60 (MIcroprotein that Negatively regulates ASsembly of the pre-60S ribosomal subunit), a 130-amino acid protein co-encoded with the human pre-mRNA splicing regulator and tumor suppressor protein RBM10. MINAS-60 localizes to the nucleolus, where it associates with multiple pre-60S assembly factors. Depletion of MINAS-60 increases the amount of mature 60S ribosomal subunit in the cytoplasm and, consequently, upregulates global protein synthesis and cell proliferation. Mechanistically, we show that MINAS-60 represses late-stage pre-60S assembly and export of the mature 60S ribosome subunit to the cytoplasm. Together, these results implicate MINAS-60 as a repressor of ribosome biogenesis that acts as a checkpoint for the maturation of the large subunit (LSU). More broadly, the RBM10 transcript encodes two sequence-independent proteins that inhibit cell proliferation via different molecular mechanisms, expanding existing models of multicistronic human gene functions.

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Noncanonical open reading frames encode functional proteins essential for cancer cell survival

Cited by 112 publications

References 70 publications

Overlapping genes in natural and engineered genomes

Overlapping genes in natural and engineered genomes

De novo birth of functional, human-specific microproteins

Nascent alt-protein chemoproteomics reveals a repressor of ribosome biogenesis

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