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EMBO J. 2019 Feb 1;38(3). pii: e99128. doi: 10.15252/embj.201899128. Epub 2018 Dec 7.

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

Author information

1
Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
2
Biochemistry and Biophysics Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA j.hogg@nih.gov.

Abstract

The human nonsense-mediated mRNA decay pathway (NMD) performs quality control and regulatory functions within complex post-transcriptional regulatory networks. In addition to degradation-promoting factors, efficient and accurate detection of NMD substrates involves proteins that safeguard normal mRNAs. Here, we identify hnRNP L as a factor that protects mRNAs with NMD-inducing features including long 3'UTRs. Using biochemical and transcriptome-wide approaches, we provide evidence that the susceptibility of a given transcript to NMD can be modulated by its 3'UTR length and ability to recruit hnRNP L. Integrating these findings with the previously defined role of polypyrimidine tract binding protein 1 in NMD evasion enables enhanced prediction of transcript susceptibility to NMD. Unexpectedly, this system is subverted in B cell lymphomas harboring translocations that produce BCL2:IGH fusion mRNAs. CRISPR/Cas9 deletion of hnRNP L binding sites near the BCL2 stop codon reduces expression of the fusion mRNAs and induces apoptosis. Together, our data indicate that protection by hnRNP L overrides the presence of multiple 3'UTR introns, allowing these aberrant mRNAs to evade NMD and promoting BCL2 overexpression and neoplasia.

KEYWORDS:

B cell lymphoma; BCL2; UPF1; hnRNP L; nonsenseā€mediated mRNA decay

PMID:
30530525
PMCID:
PMC6356069
[Available on 2020-02-01]
DOI:
10.15252/embj.201899128

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