Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Concept Videos

RNA Splicing01:32

RNA Splicing

Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
RNA Splicing01:32

RNA Splicing

Splicing is the process by which eukaryotic RNA is edited before its translation into protein. The RNA strand transcribed from eukaryotic DNA is called the primary transcript. The primary transcripts that become mRNAs are called precursor messenger RNAs (pre-mRNAs). Eukaryotic pre-mRNA contains alternating sequences of exons and introns. Exons are nucleotide sequences that code for proteins, whereas introns are the non-coding regions. In RNA splicing, introns are removed and exons are bonded...
Nuclear Export of mRNA02:31

Nuclear Export of mRNA

Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Alternative RNA Splicing02:18

Alternative RNA Splicing

Alternative RNA splicing is the regulated splicing of exons and introns to produce different mature mRNAs from a single pre-mRNA. Unlike in constitutive splicing where a single gene produces a single type of mRNA, alternative splicing allows an organism to produce multiple proteins from a single gene and plays an important role in protein diversity.
There are five types of alternative RNA splicing that vary in the ways the pre-mRNA segments are removed or retained in the mature mRNA. The first...
Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Long-read cDNA sequencing reveals novel isoforms and spliceosome-mutant-enriched transcripts in AML and MDS.

bioRxiv : the preprint server for biology·2026
Same author

U2af1<sup>S34F</sup> and U2af1<sup>Q157R</sup> myeloid neoplasm-associated hotspot mutations induce distinct hematopoietic phenotypes in mice.

Leukemia·2026
Same author

Sialylated CD43 forms a glyco-immune barrier that restrains antileukemic immunity.

Science (New York, N.Y.)·2026
Same author

Modeling the evolutionary dynamics of clonal hematopoiesis.

Nature genetics·2026
Same author

Sensitivity to ATR-CHK1 pathway inhibition in AML/MDS is enhanced by <i>SRSF2</i> mutations and reduced by RUNX1 loss.

bioRxiv : the preprint server for biology·2025
Same author

Germline genetic variation impacts clonal hematopoiesis landscape and progression to malignancy.

Nature genetics·2025

Related Experiment Video

Updated: Jun 8, 2026

Detection of Alternative Splicing During Epithelial-Mesenchymal Transition
11:48

Detection of Alternative Splicing During Epithelial-Mesenchymal Transition

Published on: October 9, 2014

13.5K

Nonsense-Mediated RNA Decay Is a Targetable Vulnerability in Splicing Factor Mutant Myeloid Neoplasms by Enhancing

Claudia Cabrera Pastrana1, Sridhar Nonavinkere Srivatsan1, Michael O Alberti2

  • 1Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri.

Cancer Research
|April 9, 2026
PubMed
Summary

Targeting the nonsense-mediated RNA decay (NMD) pathway, which degrades faulty transcripts, shows therapeutic potential for myeloid neoplasms with splicing factor mutations. Inhibiting SMG1 kinase in vivo demonstrates NMD as a vulnerability, offering a new treatment strategy.

More Related Videos

Using the E1A Minigene Tool to Study mRNA Splicing Changes
10:25

Using the E1A Minigene Tool to Study mRNA Splicing Changes

Published on: April 22, 2021

5.7K
A Reporter Based Cellular Assay for Monitoring Splicing Efficiency
08:53

A Reporter Based Cellular Assay for Monitoring Splicing Efficiency

Published on: September 15, 2021

3.4K

Related Experiment Videos

Last Updated: Jun 8, 2026

Detection of Alternative Splicing During Epithelial-Mesenchymal Transition
11:48

Detection of Alternative Splicing During Epithelial-Mesenchymal Transition

Published on: October 9, 2014

13.5K
Using the E1A Minigene Tool to Study mRNA Splicing Changes
10:25

Using the E1A Minigene Tool to Study mRNA Splicing Changes

Published on: April 22, 2021

5.7K
A Reporter Based Cellular Assay for Monitoring Splicing Efficiency
08:53

A Reporter Based Cellular Assay for Monitoring Splicing Efficiency

Published on: September 15, 2021

3.4K

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mutant spliceosome proteins in myeloid neoplasms cause aberrant RNA splicing, producing nonsense transcripts.
  • The nonsense-mediated RNA decay (NMD) pathway degrades these nonsense transcripts.
  • In vitro studies show NMD inhibition preferentially kills cells with spliceosome mutations.

Purpose of the Study:

  • To provide in vivo evidence that NMD is a therapeutic vulnerability in splicing factor mutant myeloid neoplasms.
  • To investigate the effects of SMG1 kinase inhibition (SMG1i) on these cells in vivo.

Main Methods:

  • Utilized a SMG1 kinase inhibitor (SMG1i) in mouse acute myeloid leukemia and human K562 cell line models.
  • Assessed cellular sensitivity to SMG1i in wild-type versus spliceosome mutant cells.
  • Measured R-loop levels, DNA damage, and NMD transcript isoforms following SMG1i treatment.
  • Investigated the role of R-loops and DNA repair genes (ATR, RAD51) in treatment response.

Main Results:

  • Spliceosome mutant cells showed increased sensitivity to in vivo SMG1i compared to wild-type cells.
  • SMG1i disrupted NMD, increasing R-loop accumulation and DNA damage, particularly in mutant cells.
  • Degrading R-loops rescued mutant cells from SMG1i-induced death.
  • SMG1i increased NMD transcript isoforms enriched for DNA repair genes; co-inhibition of ATR or RAD51 enhanced cell death.

Conclusions:

  • In vivo inhibition of NMD via SMG1 kinase is a viable therapeutic strategy for myeloid neoplasms with aberrant splicing.
  • R-loop accumulation and DNA damage are key mechanisms mediating the anti-leukemia effects of NMD inhibition.
  • Combined targeting of NMD and DNA repair pathways presents a promising approach for treating these malignancies.