Related Experiment Video
Updated: Nov 19, 2025
09:37
An Integrated Approach for Microprotein Identification and Sequence Analysis
Published on: July 12, 2022
3.8K
Noncanonical open reading frames encode functional proteins essential for cancer cell survival.
John R Prensner1,2,3, Oana M Enache1, Victor Luria4
1Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Nature Biotechnology
|January 29, 2021
Summary
Many noncanonical open reading frames (ORFs) encode biologically active proteins, with some showing essentiality in cancer cell lines. One such protein, GREP1, is a potential therapeutic target in breast cancer.
Area of Science:
- Genomics
- Proteomics
- Cancer Biology
Background:
- Genomic analyses predict numerous noncanonical open reading frames (ORFs) in the human genome, but their functional relevance remains largely unexplored.
- Experimental interrogation of 553 candidate noncanonical ORFs was performed to assess their biological activity and protein-coding potential.
Discussion:
- 57 noncanonical ORFs induced viability defects upon knockout in human cancer cell lines, suggesting essential functions.
- Evidence of protein expression was observed for 257 candidates, and 401 induced gene expression changes, indicating active biological roles.
- Clustered regularly interspaced short palindromic repeat (CRISPR) tiling and start codon mutagenesis confirmed that observed effects were translation-dependent, not RNA-mediated.
Key Insights:
- The noncanonical ORF G029442, renamed glycine-rich extracellular protein-1 (GREP1), encodes a secreted protein highly expressed in breast cancer.
- GREP1 knockout demonstrated preferential essentiality in breast cancer-derived cell lines, highlighting its specific role in this cancer type.
- GREP1 expression correlates with increased levels of the oncogenic cytokine GDF15, which can rescue growth inhibition caused by GREP1 knockout.
Outlook:
- Noncanonical ORFs represent a significant source of novel, biologically active proteins with potential therapeutic applications.
- GREP1 and its associated pathway involving GDF15 present a promising avenue for targeted breast cancer therapies.
- Further research into noncanonical ORFs could uncover new drug targets and therapeutic strategies across various cancers.
More Related Videos
07:38Mass Spectrometry-Based Proteomics Analyses Using the OpenProt Database to Unveil Novel Proteins Translated from Non-Canonical Open Reading Frames
Published on: April 11, 2019
13.1K
08:23De novo Identification of Actively Translated Open Reading Frames with Ribosome Profiling Data
Published on: February 18, 2022
3.9K
Related Concept Videos
01:33Cancer-Critical Genes I: Proto-oncogenes
9.8K
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
9.8K
03:03mTOR Signaling and Cancer Progression
4.1K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
4.1K
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
8.7K
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
8.7K
02:53Adaptive Mechanisms in Cancer Cells
6.2K
Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
6.2K
02:28Leaky Scanning
5.4K
During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.4K
02:26Protein Networks
4.3K
An organism can have thousands of different proteins, and these proteins must cooperate to ensure the health of an organism. Proteins bind to other proteins and form complexes to carry out their functions. Many proteins interact with multiple other proteins creating a complex network of protein interactions.
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
These interactions can be represented through maps depicting protein-protein interaction networks, represented as nodes and edges. Nodes are circles that are representative of a protein,...
4.3K