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Related Concept Videos

Alternative RNA Splicing02:18

Alternative RNA Splicing

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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...
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RNA Splicing01:32

RNA Splicing

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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...
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Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

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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.
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Cancer-Critical Genes II: Tumor Suppressor Genes01:05

Cancer-Critical Genes II: Tumor Suppressor Genes

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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.
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Cancer-Critical Genes I: Proto-oncogenes01:33

Cancer-Critical Genes I: Proto-oncogenes

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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.
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Such genes that act...
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Loss of Tumor Suppressor Gene Functions01:12

Loss of Tumor Suppressor Gene Functions

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Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
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Related Experiment Video

Updated: Jun 25, 2025

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

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ACLY alternative splicing correlates with cancer phenotypes.

Julianna G Supplee1, Hayley C Affronti2, Richard Duan2

  • 1Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

The Journal of Biological Chemistry
|May 30, 2024
PubMed
Summary

ATP-citrate lyase (ACLY) splicing produces two isoforms, but functional differences remain unclear. Despite altered splicing in cancers, neither isoform impacts cell metabolism, stability, or tumor growth, suggesting its role in cancer requires further investigation.

Keywords:
ATP-citrate lyaseAlternative splicingCancerEpithelial Splicing Regulatory Protein 1IsoformsMetabolismTCGA

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Detection of Alternative Splicing During Epithelial-Mesenchymal Transition
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Identification of Alternative Splicing and Polyadenylation in RNA-seq Data
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Identification of Alternative Splicing and Polyadenylation in RNA-seq Data

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • ATP-citrate lyase (ACLY) is crucial for linking carbohydrate and lipid metabolism, supplying acetyl-CoA for cellular processes.
  • ACLY exists as two splice isoforms: a full-length 'long' form and a 'short' form lacking exon 14.
  • Altered splicing of ACLY exon 14 is observed in various cancers, correlating with poorer survival, prompting investigation into isoform-specific functions.

Purpose of the Study:

  • To investigate potential biochemical and functional differences between ACLY long and short isoforms.
  • To explore the impact of ACLY exon 14 splicing on cellular metabolism, stability, and cancer progression.
  • To identify regulatory mechanisms of ACLY splicing and its correlation with tumor immune microenvironments.

Main Methods:

  • In vitro assays to assess enzymatic activity and stability of ACLY isoforms and phosphomutants.
  • Re-expression studies in Acly knockout cells to evaluate isoform function in fatty acid synthesis and histone acetylation.
  • Analysis of transcriptomic data, mouse models of cancer, and correlation studies with splicing regulatory factors.

Main Results:

  • No discernible differences in enzymatic activity or stability were found between ACLY isoforms or phosphomutants in vitro.
  • Both isoforms effectively rescued ACLY functions, including fatty acid synthesis and histone acetylation, in knockout cells.
  • Deletion of exon 14 in mice did not affect development or metabolic physiology, nor did it alter tumor burden in a cancer model.
  • ACLY splicing is regulated by ESRP1, and both ESRP1 expression and ACLY splicing patterns correlate with tumor immune signatures.

Conclusions:

  • Despite altered splicing patterns in cancer, no functional differences were identified between ACLY isoforms in vitro or in vivo.
  • The splicing of ACLY exon 14 is regulated by ESRP1 and is associated with specific immune signatures in tumors.
  • The functional significance of ACLY isoform variation in cancer remains elusive and warrants further research.