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Characterization of the aberrant splicing of MAP3K7 induced by cancer-associated SF3B1 mutation

Zhuang Li1,2, Bo Zhao1,2, Yueru Shi1,2

  • 1Laboratory of Cancer Biology, China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China.

Journal of Biochemistry
|March 22, 2021
PubMed

Insights

Cancer-associated SF3B1 mutations drive aberrant RNA splicing, promoting tumorigenesis. This study reveals how these mutations affect MAP3K7 splicing and its targeting by nonsense-mediated decay.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • The splicing factor SF3B1 is frequently mutated in cancers, leading to aberrant RNA splicing.
  • Aberrant splicing of specific transcripts, such as MAP3K7, contributes to tumor development.

Purpose of the Study:

  • To investigate the mechanisms by which cancer-associated SF3B1 mutations cause aberrant MAP3K7 splicing.
  • To identify the sequence features and regulatory pathways involved in this aberrant splicing process.

Main Methods:

  • Utilized HEK293T cells transfected with mutated SF3B1 (K700E).
  • Applied cycloheximide treatment to assess transcript stability and nonsense-mediated decay.
  • Analyzed splice site usage, branchpoint sequences, and polypyrimidine tract requirements.

Main Results:

  • Identified a premature termination codon in the aberrantly spliced MAP3K7 transcript.
  • Demonstrated that the aberrant MAP3K7 transcript is targeted by nonsense-mediated decay.
  • Revealed that aberrant MAP3K7 splicing requires both normal and alternative polypyrimidine tracts, along with aberrant 3' splice sites and alternative branchpoint sequences.
  • Confirmed that other cancer-associated SF3B1 mutations induce similar MAP3K7 aberrant splicing.

Conclusions:

  • Cancer-associated SF3B1 mutations induce aberrant MAP3K7 splicing through specific sequence features.
  • Alternative polypyrimidine tracts play a crucial role in SF3B1-mediated aberrant splicing in disease contexts.
  • This research deepens the understanding of splicing factor mutations in cancer pathogenesis.
Keywords:
3ʹRNA splicingbranch point sequencenonsense-mediated decaypolypyrimidine tractsplice site

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