scholarly journals Discovery of a small protein-encoding cis-regulatory overlapping gene of the tumor suppressor gene Scribble in humans

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yuhta Nomura ◽  
Naoshi Dohmae
Keyword(s):  
Tumor Suppressor ◽  
Gene Annotation ◽  
Regulatory Elements ◽  
Suppressor Gene ◽  
Open Reading Frames ◽  
Protein Coding ◽  
Proteomic Data ◽  
Biochemical Analyses ◽  
Safe Mechanism ◽  
Fail Safe

AbstractIntensive gene annotation has revealed many functional and regulatory elements in the human genome. Although eukaryotic protein-coding genes are generally transcribed into monocistronic mRNAs, recent studies have discovered additional short open reading frames (sORFs) in mRNAs. Here, we performed proteogenomic data mining for hidden proteins categorized into sORF-encoded polypeptides (SEPs) in human cancers. We identified a new SEP-encoding overlapping sORF (oORF) on the cell polarity determinant Scribble (SCRIB) that is considered a proto-oncogene with tumor suppressor function in Hippo-YAP/TAZ, MAPK/ERK, and PI3K/Akt/mTOR signaling. Reanalysis of clinical human proteomic data revealed translational dysregulation of both SCRIB and its oORF, oSCRIB, during carcinogenesis. Biochemical analyses suggested that the translatable oSCRIB constitutively limits the capacity of eukaryotic ribosomes to translate the downstream SCRIB. These findings provide a new example of cis-regulatory oORFs that function as a ribosomal roadblock and potentially serve as a fail-safe mechanism to normal cells for non-excessive downstream gene expression, which is hijacked in cancer.

In Silico Analysis of the CST6 Tumor Suppressor Gene

2013 ◽  
Vol 2 (3) ◽  
pp. 42-58
Author(s):  
Athanasia Pavlopoulou ◽  
Georgios Tsaramirsis
Keyword(s):  
Tumor Suppressor ◽  
Splice Variants ◽  
Cpg Island ◽  
Mammalian Species ◽  
Gene Promoter ◽  
In Silico Analysis ◽  
Regulatory Elements ◽  
Suppressor Gene ◽  
Differentially Expressed ◽  
Gene Encoding

The gene encoding cystatin E/M, CST6, is a Class II tumor suppressor. Using bioinformatics tools for database mining and virtual gene expression profiling, the authors showed that CST6 is differentially expressed in various types of cancer. Moreover, epigenetic silencing mediated by hypermethylation of the CpG island located at the CST6 promoter was found to be conserved in mammalian species. Comprehensive analyses of animal genomes led to the identification of novel CST6 transcript orthologs and splice variants that enabled us to trace the evolutionary origin of CST6. Moreover, eight novel and potentially regulatory SNPs were identified in CST6 gene. Conserved cancer-relevant regulatory elements were identified in the CST6 gene promoter. In addition, miRNAs that are differentially expressed in human cancers were identified as putative posttranscriptional regulators of CST6. Collectively, the authors suggest that expression of CST6 in normal and cancer cells is coordinately regulated by genomic, transcriptional and post-transcriptional mechanisms.

scholarly journals A community-driven roadmap to advance research on translated open reading frames detected by Ribo-seq

2021 ◽  
Author(s):  
Jonathan M Mudge ◽  
Jorge Ruiz-Orera ◽  
John R Prensner ◽  
Marie A Brunet ◽  
Jose Manuel Gonzalez ◽  
...  
Keyword(s):  
Gene Annotation ◽  
Ribosome Profiling ◽  
Open Reading Frames ◽  
Untranslated Regions ◽  
Biological Databases ◽  
Protein Coding ◽  
Circular Problem ◽  
Advance Research ◽  
Non Coding Rnas ◽  
Reading Frames

Ribosome profiling (Ribo-seq) has catalyzed a paradigm shift in our understanding of the translational vocabulary of the human genome, discovering thousands of translated open reading frames (ORFs) within long non-coding RNAs and presumed untranslated regions of protein-coding genes. However, reference gene annotation projects have been circumspect in their incorporation of these ORFs due to uncertainties about their experimental reproducibility and physiological roles. Yet, it is indisputable that certain Ribo-seq ORFs make stable proteins, others mediate gene regulation, and many have medical implications. Ultimately, the absence of standardized ORF annotation has created a circular problem: while Ribo-seq ORFs remain unannotated by reference biological databases, this lack of characterisation will thwart research efforts examining their roles. Here, we outline the initial stages of a community-led effort supported by GENCODE / Ensembl, HGNC and UniProt to produce a consolidated catalog of human Ribo-seq ORFs.

scholarly journals Disrupting upstream translation in mRNAs leads to loss-of-function associated with human disease

2020 ◽  
Author(s):  
David S.M. Lee ◽  
Joseph Park ◽  
Andrew Kromer ◽  
Daniel J. Rader ◽  
Marylyn D. Ritchie ◽  
...  
Keyword(s):  
Biological Significance ◽  
Regulatory Elements ◽  
Ribosome Profiling ◽  
Open Reading Frames ◽  
Loss Of Function ◽  
Protein Coding ◽  
Stop Codons ◽  
Human Genes ◽  
Strong Negative Selection ◽  
Disease Associations

ABSTRACTRibosome-profiling has uncovered pervasive translation in 5’UTRs, however the biological significance of this phenomenon remains unclear. Using genetic variation from 71,702 human genomes, we assess patterns of selection in translated upstream open reading frames (uORFs) in 5’UTRs. We show that uORF variants introducing new stop codons, or strengthening existing stop codons, are under strong negative selection comparable to protein-coding missense variants. Using these variants, we map and validate new gene-disease associations in two independent biobanks containing exome sequencing from 10,900 and 32,268 individuals respectively, and demonstrate their impact on gene expression in human cells. Our results establish new mechanisms relating uORF variation to loss-of-function of downstream genes, and demonstrate that translated uORFs are genetically constrained regulatory elements in 40% of human genes.

scholarly journals Developmental regulation of Canonical and small ORF translation from mRNAs

2019 ◽  
Author(s):  
Pedro Patraquim ◽  
Muhammad Ali S. Mumtaz ◽  
Jose I. Pueyo ◽  
Julie L. Aspden ◽  
J.P. Couso
Keyword(s):  
Translational Regulation ◽  
Developmental Regulation ◽  
Open Reading Frames ◽  
Main Function ◽  
Protein Coding ◽  
Proteomic Data ◽  
Short Orfs ◽  
Highly Correlated ◽  
Small Orfs

ABSTRACTRibosomal profiling has revealed the translation of thousands of sequences outside of annotated protein-coding genes, including small Open Reading Frames of less than 100 codons, and the translational regulation of many genes. Here we have improved Poly-Ribo-Seq and applied it to Drosophila melanogaster embryos to extend the catalogue of in-vivo translated small ORFs, and to reveal the translational regulation of both small and canonical ORFs from mRNAs across embryogenesis. We obtain highly correlated samples across five embryonic stages, with close to 500 million putative ribosomal footprints mapped to mRNAs, and compared them to existing Ribo-Seq and proteomic data. Our analysis reveals, for the first time in Drosophila, footprints mapping to codons in a phased pattern, the hallmark of productive translation, and we propose a simple binomial probability metric to ascertain translation probability. However, our results also reveal reproducible ribosomal binding apparently not resulting in productive translation. This non-productive ribosomal binding seems to be especially prevalent amongst upstream short ORFs located in the 5’ mRNA Leaders, and amongst canonical ORFs during the activation of the zygotic translatome at the maternal to zygotic transition. We suggest that this non-productive ribosomal binding might be due to cis-regulatory ribosomal binding, and to defective ribosomal scanning of ORFs outside periods of productive translation. Finally, we show that the main function of upstream short ORFs is to buffer the translation of canonical ORFs, and that in general small ORFs in mRNAs display Poly-Ribo-Seq and bioinformatics markers compatible with an evolutionary transitory state towards full coding function.

CENP-C: An oncogene or tumor suppressor gene? A possible new tumor marker

2001 ◽  
Vol 120 (5) ◽  
pp. A299-A299
Author(s):  
D KAZANOV ◽  
B STERN ◽  
W PYERIN ◽  
O BOECHER ◽  
H STRUL ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Marker ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene
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