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hnRNP L-dependent protection of normal mRNAs from NMD subverts quality control in B cell lymphoma

Aparna Kishor1, Zhiyun Ge1, J Robert Hogg2

  • 1Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.

The EMBO Journal
|December 12, 2018
PubMed

Insights

hnRNP L protects normal mRNAs from nonsense-mediated decay (NMD). Aberrant BCL2:IGH fusion mRNAs in lymphoma evade NMD by recruiting hnRNP L, promoting cancer.

Area of Science:

  • Molecular Biology
  • RNA Biology
  • Cancer Biology

Background:

  • The nonsense-mediated mRNA decay (NMD) pathway is crucial for cellular quality control and gene regulation.
  • NMD targets aberrant mRNAs, but regulatory mechanisms also protect normal transcripts.

Purpose of the Study:

  • To identify factors that protect mRNAs from NMD.
  • To investigate the role of hnRNP L in NMD regulation and its subversion in B cell lymphomas.

Main Methods:

  • Biochemical assays to study protein-RNA interactions.
  • Transcriptome-wide analyses to assess NMD susceptibility.
  • CRISPR/Cas9 gene editing to investigate functional consequences.

Main Results:

  • hnRNP L protects mRNAs with NMD-inducing features, such as long 3'UTRs.
  • Transcript susceptibility to NMD is modulated by 3'UTR length and hnRNP L recruitment.
  • BCL2:IGH fusion mRNAs in lymphoma evade NMD via hnRNP L binding, leading to BCL2 overexpression.
  • hnRNP L binding site deletion reduces fusion mRNA levels and induces apoptosis.

Conclusions:

  • hnRNP L acts as a key protective factor against NMD, overriding other regulatory elements.
  • Subversion of the hnRNP L-mediated NMD evasion mechanism contributes to B cell lymphoma development.
  • Targeting hnRNP L interactions offers a potential therapeutic strategy for B cell lymphomas.
Keywords:
B cell lymphomaBCL2UPF1hnRNP Lnonsense‐mediated mRNA decay

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