The oncomicropeptide APPLE promotes hematopoietic malignancy by enhancing translation initiation

Sun, Lin-Yu; Wang, Wen-Tao; Han, Cai; Huang, Wei; Sun, Yu-Meng; Fang, Ke; Zeng, Zhan-Cheng; Yang, Qianqian; Pan, Qi; Chen, Tianqi; Luo, Xue-Qun; Chen, Yue‐Qin

doi:10.1016/j.molcel.2021.08.033

Cited by 54 publications

(46 citation statements)

References 75 publications

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“…Thirty days after inoculation, xenografted mice were sacrificed for analysis. Human cell engraftment (GFP + cell populations) in bone marrow was evaluated by flow cytometry 82 , 83 . The remaining mice were used to perform the survival assay.…”

Section: Methodsmentioning

confidence: 99%

The snoRNA-like lncRNA LNC-SNO49AB drives leukemia by activating the RNA-editing enzyme ADAR1

et al. 2022

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Long noncoding RNAs (lncRNAs) are usually 5′ capped and 3′ polyadenylated, similar to most typical mRNAs. However, recent studies revealed a type of snoRNA-related lncRNA with unique structures, leading to questions on how they are processed and how they work. Here, we identify a novel snoRNA-related lncRNA named LNC-SNO49AB containing two C/D box snoRNA sequences, SNORD49A and SNORD49B; and show that LNC-SNO49AB represents an unreported type of lncRNA with a 5′-end m7G and a 3′-end snoRNA structure. LNC-SNO49AB was found highly expressed in leukemia patient samples, and silencing LNC-SNO49AB dramatically suppressed leukemia progression in vitro and in vivo. Subcellular location indicated that the LNC-SNO49AB is mainly located in nucleolus and interacted with the nucleolar protein fibrillarin. However, we found that LNC-SNO49AB does not play a role in 2′-O-methylation regulation, a classical function of snoRNA; instead, its snoRNA structure affected the lncRNA stability. We further demonstrated that LNC-SNO49AB could directly bind to the adenosine deaminase acting on RNA 1(ADAR1) and promoted its homodimerization followed by a high RNA A-to-I editing activity. Transcriptome profiling shows that LNC-SNO49AB and ADAR1 knockdown respectively share very similar patterns of RNA modification change in downstream signaling pathways, especially in cell cycle pathways. These findings suggest a previously unknown class of snoRNA-related lncRNAs, which function via a manner in nucleolus independently on snoRNA-guide rRNA modification. This is the first report that a lncRNA regulates genome-wide RNA A-to-I editing by enhancing ADAR1 dimerization to facilitate hematopoietic malignancy, suggesting that LNC-SNO49AB may be a novel target in therapy directed to leukemia.

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Section: Methodsmentioning

confidence: 99%

The snoRNA-like lncRNA LNC-SNO49AB drives leukemia by activating the RNA-editing enzyme ADAR1

et al. 2022

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“…In a recent study, Sun et al (2021), identified an oncomicropeptide APPLE (90 aa) encoded by the non-coding RNA ASH1L-AS1 using a combinatorial approach of ribosome profiling, mass spectrometry and RNA-seq analyses. The authors showed that APPLE is overexpressed in subtypes of acute myeloid leukaemia and led to a poor prognosis.…”

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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“…An oncomicropeptide, APPLE, encoded by ASH1L-AS1, served as a translation initiation regulator in AML. It facilitated PABPC1-eIF4G interaction to induce mRNA circularization and eIF4F complex assembly, and in turn, the PABPC1-APPLE-eIF4G axis met the requirement of oncoprotein synthesis [ 92 ] ( Figure 5 e).…”

Section: Functions and Mechanisms Of Ncrna-encoded Peptides/proteins ...mentioning

confidence: 99%

A Whole New Comprehension about ncRNA-Encoded Peptides/Proteins in Cancers

Chen

Shen²,

Nie³

et al. 2022

Cancers

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It is generally considered that non-coding RNAs do not encode proteins; however, more recently, studies have shown that lncRNAs and circRNAs have ORFs which are regions that code for peptides/protein. On account of the lack of 5’cap structure, translation of circRNAs is driven by IRESs, m6A modification or through rolling amplification. An increasing body of evidence have revealed different functions and mechanisms of ncRNA-encoded peptides/proteins in cancers, including regulation of signal transduction (Wnt/β-catenin signaling, AKT-related signaling, MAPK signaling and other signaling), cellular metabolism (Glucose metabolism and Lipid metabolism), protein stability, transcriptional regulation, posttranscriptional regulation (regulation of RNA stability, mRNA splicing and translation initiation). In addition, we conclude the existing detection technologies and the potential of clinical applications in cancer therapy.

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The oncomicropeptide APPLE promotes hematopoietic malignancy by enhancing translation initiation

Cited by 54 publications

References 75 publications

The snoRNA-like lncRNA LNC-SNO49AB drives leukemia by activating the RNA-editing enzyme ADAR1

The snoRNA-like lncRNA LNC-SNO49AB drives leukemia by activating the RNA-editing enzyme ADAR1

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

A Whole New Comprehension about ncRNA-Encoded Peptides/Proteins in Cancers

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