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Related Concept Videos

RNA Splicing01:32

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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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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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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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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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Since the discovery of the two BER pathways, there has been a debate about how a cell chooses one pathway over the other and the factors determining this selection. Numerous in vitro experiments have pointed out multiple determinants for the sub-pathway selection. These are:
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Defining Splicing Factor Requirements for Androgen Receptor Variant Synthesis in Advanced Prostate Cancer.

Laura Walker1, Ruaridh Duncan1, Beth Adamson1

  • 1Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom.

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|September 30, 2024
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Identifying regulators of androgen receptor variant (AR-V) splicing is crucial for overcoming treatment resistance in prostate cancer. This study identified MFAP1 and CWC22 as key splicing factors for AR-V generation, offering new therapeutic targets for castration-resistant prostate cancer.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Androgen receptor (AR)-targeted therapies are challenged by treatment resistance in prostate cancer.
  • Castration-resistant prostate cancer (CRPC) often involves constitutively active AR variants (AR-Vs) that drive tumor progression.
  • Limited understanding of AR-V splicing regulation hinders the development of novel therapeutic strategies.

Purpose of the Study:

  • To identify novel splicing factors regulating the synthesis of AR variants (AR-Vs) in prostate cancer.
  • To uncover potential therapeutic targets for overcoming resistance to AR-targeted therapies in CRPC.
  • To investigate the functional impact of AR-V splicing regulators in CRPC models.

Main Methods:

  • A bespoke CRISPR screen was employed to systematically profile splicing factor requirements for AR-V synthesis.
  • Depletion of identified splicing factors (MFAP1, CWC22) was performed in CRPC models.
  • Global transcriptomic analysis was conducted on MFAP1-depleted cells.

Main Results:

  • MFAP1 and CWC22 were identified as essential for AR-V mRNA transcript generation.
  • Depletion of MFAP1 and CWC22 reduced AR-V protein levels and CRPC cell proliferation.
  • MFAP1 downregulation sensitized prostate cancer cells to ionizing radiation, impacting DNA damage response pathways.

Conclusions:

  • MFAP1 and CWC22 are critical regulators of pathogenic AR splicing in prostate cancer.
  • Targeting AR-V splicing represents a promising therapeutic strategy for CRPC.
  • MFAP1 inhibition may enhance sensitivity to DNA-damaging agents like ionizing radiation in CRPC treatment.