MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis

Area of Science:

• Oncology
• Molecular Biology
• Gene Regulation

Background:

• MYC overexpression is common in human cancers, linked to proliferation and poor prognosis.
• MYC's role in tumorigenesis is complex, with key effectors largely unknown.
• MYC regulates gene expression by binding to active promoters.

Purpose of the Study:

• To identify critical MYC effectors in lymphomagenesis.
• To investigate MYC's role in regulating RNA splicing.
• To understand how MYC influences small nuclear ribonucleoprotein particle biogenesis.

Main Methods:

• Utilized Eµ-myc transgenic mice for lymphomagenesis studies.
• Analyzed MYC's direct transcriptional targets, focusing on spliceosome assembly genes.
• Employed antisense oligonucleotides to assess splicing defect contributions.

Main Results:

• MYC directly upregulates core small nuclear ribonucleoprotein particle assembly genes, including PRMT5.
• This regulation is essential for spliceosome biogenesis, splicing fidelity, cell survival, and proliferation.
• Perturbation of the MYC-PRMT5 axis causes splicing defects (intron retention/exon skipping) in specific pre-mRNAs.

Conclusions:

• MYC safeguards pre-messenger RNA splicing fidelity as a critical step in lymphomagenesis.
• Beyond transcription and translation, MYC's role in splicing is vital for cancer development.
• Splicing defects resulting from MYC-PRMT5 axis disruption contribute to anti-proliferative and apoptotic phenotypes.