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Related Concept Videos

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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In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
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Alternative RNA Splicing02:18

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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.
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Using the E1A Minigene Tool to Study mRNA Splicing Changes
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Hypoxia-driven splicing into noncoding isoforms regulates the DNA damage response.

Danish Memon1, Keren Dawson1, Christopher Sf Smowton2

  • 1RNA Biology Group, CRUK Manchester Institute, The University of Manchester, Manchester, UK.

NPJ Genomic Medicine
|May 9, 2017
PubMed
Summary
This summary is machine-generated.

Tumour hypoxia alters gene expression through alternative splicing, impacting DNA damage repair pathways. This study reveals a new role for splicing in hypoxia-driven cancer progression and therapy resistance.

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Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genomics

Background:

  • Tumour hypoxia is linked to poor patient outcomes and treatment resistance.
  • Hypoxia drives gene expression changes via transcription factors like HIF1/2/3α.
  • Hypoxia affects cellular pathways and phenotype.

Purpose of the Study:

  • To investigate hypoxia-induced changes in transcript architecture due to alternative splicing.
  • To identify specific genes and pathways affected by alternative splicing under hypoxic conditions.

Main Methods:

  • Utilized sample-specific annotation to analyze alternative splicing in hypoxic cells.
  • Generated in vivo time-course data under reduced oxygenation.
  • Validated findings in a large colorectal cancer cohort from The Cancer Genome Atlas (TCGA).

Main Results:

  • Identified genome-wide switching between coding and noncoding isoforms in hypoxic cells.
  • Observed significant alterations in DNA damage response (DDR) pathway components, including HDAC6 and TP53BP1, shifting towards intron retention.
  • Confirmed these splicing transitions and their enrichment in DDR pathways (Fanconi Anaemia, nucleotide excision, double-strand break repair) in a large TCGA colorectal cancer cohort.

Conclusions:

  • Hypoxia-driven alternative splicing plays a critical role in regulating the DNA damage response.
  • Alternative splicing is a key factor in understanding human disease, particularly in the context of cancer and hypoxia.
  • Findings highlight the importance of considering alternative splicing in cancer therapy and patient outcomes.