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Related Concept Videos

Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

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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.
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Gene expression can be regulated at almost every step from gene to protein. Transcription is the step that is most commonly regulated. This involves the binding of proteins to short regulatory sequences on the DNA. This association can either promote or inhibit the transcription of a gene associated with the respective sequence.
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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...
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In eukaryotic cells, transcripts made by RNA polymerase are modified and processed before exiting the nucleus. Unprocessed RNA is called precursor mRNA or pre-mRNA to distinguish it from mature mRNA.
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Nuclear protein sorting regulates nucleus composition and gene expression, crucial for determining the fate of a eukaryotic cell. Hence, the entry and exit of molecules across the nuclear envelope is a tightly controlled process. Nuclear protein sorting can be inhibited by one of the following ways: 1) masking cargo signal sequences, 2) modifying the nuclear receptor's affinity for cargo, 3) controlling the nuclear pore size, 4) retaining the cargo during its transit to the cytosol or the...
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Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
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CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

Nathan T Ross1,2, Felix Lohmann3, Seth Carbonneau1

  • 1Novartis Institutes for BioMedical Research, Cambridge, MA, USA.

Nature Chemical Biology
|December 11, 2019
PubMed
Summary

Researchers identified pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as a novel cancer target. Inhibiting CPSF3 with JTE-607 shows promise for treating acute myeloid leukemia and Ewing's sarcoma.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Cancer treatment faces challenges from resistance and tumor heterogeneity.
  • Targeting specific cancer pathways remains crucial despite advances in the post-genomic era.

Purpose of the Study:

  • To identify the molecular target of the small molecule JTE-607.
  • To investigate the therapeutic potential of targeting pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) in cancer.

Main Methods:

  • Phenotypic screening and chemical genetics were employed to identify JTE-607's target.
  • The effects of CPSF3 inhibition were analyzed in acute myeloid leukemia (AML) and Ewing's sarcoma cell lines.
  • In vivo efficacy was assessed using mouse xenograft models.

Main Results:

  • CPSF3 was identified as the target of JTE-607.
  • CPSF3 inhibition demonstrated synthetic lethality in a subset of AML and Ewing's sarcoma cells.
  • JTE-607 treatment led to altered downstream effector expression, increased apoptosis, and tumor stasis in vivo.
  • Mechanism involves impaired pre-mRNA release, read-through transcription, and R-loop formation.

Conclusions:

  • CPSF3 is a druggable target for cancer therapy.
  • Inhibition of CPSF3 presents a novel therapeutic strategy for AML and Ewing's sarcoma.
  • Targeting pre-mRNA processing offers a new avenue for cancer intervention.