Evidence map›Paper›PMID 33510483›Full record

ArticleNature biotechnology2021

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

John R Prensner, Oana M Enache, Victor Luria, Karsten Krug, Karl R Clauser, Joshua M Dempster, Amir Karger, Li Wang, Karolina Stumbraite, Vickie M Wang and 16 more

Open access · greenAbstract readLetter
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature biotechnology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 123 papers.

0numbers the graph read from it
0cells of the map it votes in
123citing papers in PubMed
9.7field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

123 citing papers in PubMed, 184 citations in OpenAlex.

  1. Review
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  3. The diverse functions of viral microproteins.bioRxiv : the preprint server for biology · 2026
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  13. Genetic interaction betweenbioRxiv : the preprint server for biology · 2026
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  14. Genetic interaction betweenResearch square · 2026
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  15. Review
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  17. Article
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  19. Article
  20. Article

63 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

26 authors at 3 institutions in 1 country.

John R PrensnerBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Oana M EnacheBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Victor LuriaDepartment of Systems Biology, Harvard Medical School, Boston, MA, USA.
Karsten KrugBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Karl R ClauserBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Joshua M DempsterBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Amir KargerIT-Research Computing, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-4561-3850
Li WangBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Karolina StumbraiteBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Vickie M WangBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Ginevra BottaBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Nicholas J LyonsBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Amy GoodaleBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Zohra KalaniBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Briana FritchmanBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Adam BrownBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Douglas AlanBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Thomas GreenBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Xiaoping YangBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Jacob D JaffeBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-9845-1210
Jennifer A RothBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Federica PiccioniBroad Institute of Harvard and MIT, Cambridge, MA, USA.
Marc W KirschnerDepartment of Systems Biology, Harvard Medical School, Boston, MA, USA.
Zhe JiDepartment of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-1809-8099
David E RootBroad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-5122-861X
Todd R GolubBroad Institute of Harvard and MIT, Cambridge, MA, USA. golub@broadinstitute.org.ORCID http://orcid.org/0000-0003-0113-2403
Broad Institute · USHarvard University · USNorthwestern University · US

Funding

Training Program in Nervous System TumorsK12CA090354 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI PLOTKIN, SCOTT R · 2001 to 2025
$16.3M
Systems Analysis of cell type differentiation in Xenopus developmentR01HD073104 · NICHD · HARVARD MEDICAL SCHOOL · PI KIRSCHNER, MARC WALLACE, PESHKIN, LEON · 2012 to 2022
$6.7M
Proteomics of Cell Signaling in Embryogenesis.R01HD091846 · NICHD · HARVARD MEDICAL SCHOOL · PI GYGI, STEVEN P, KIRSCHNER, MARC WALLACE · 2017 to 2021
$3.1M
Characterizing functional translation in putative 'noncoding' regions of a genome: Admin SupplR35GM138192 · NIGMS · NORTHWESTERN UNIVERSITY AT CHICAGO · PI JI, ZHE · 2020 to 2024
$2.1M
Dissect regulation of RNA translation in human cancersR00CA207865 · NCI · NORTHWESTERN UNIVERSITY AT CHICAGO · PI JI, ZHE · 2018 to 2020
$705k
NCI NIH HHS K12 CA090354NCI NIH HHS R00 CA207865NICHD NIH HHS R01 HD073104NICHD NIH HHS R01 HD091846NIGMS NIH HHS R35 GM138192
6 · The paper itself

Abstract

Although genomic analyses predict many noncanonical open reading frames (ORFs) in the human genome, it is unclear whether they encode biologically active proteins. Here we experimentally interrogated 553 candidates selected from noncanonical ORF datasets. Of these, 57 induced viability defects when knocked out in human cancer cell lines. Following ectopic expression, 257 showed evidence of protein expression and 401 induced gene expression changes. Clustered regularly interspaced short palindromic repeat (CRISPR) tiling and start codon mutagenesis indicated that their biological effects required translation as opposed to RNA-mediated effects. We found that one of these ORFs, G029442-renamed glycine-rich extracellular protein-1 (GREP1)-encodes a secreted protein highly expressed in breast cancer, and its knockout in 263 cancer cell lines showed preferential essentiality in breast cancer-derived lines. The secretome of GREP1-expressing cells has an increased abundance of the oncogenic cytokine GDF15, and GDF15 supplementation mitigated the growth-inhibitory effect of GREP1 knockout. Our experiments suggest that noncanonical ORFs can express biologically active proteins that are potential therapeutic targets.

Indexed as

Cell Line, TumorCell SurvivalClustered Regularly Interspaced Short Palindromic RepeatsHEK293 CellsHumansNeoplasm ProteinsNeoplasmsOpen Reading FramesNeoplasm Proteins

Identifiers

PMID33510483
PMCPMC8195866
OpenAlexW3125963888

What OpenQuestion holds

Textmetadata
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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.