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Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis

Author

Listed:
  • Jeffrey Vedanayagam

    (Memorial Sloan-Kettering Cancer Center)

  • Walid K. Chatila

    (Memorial Sloan-Kettering Cancer Center
    Weill Cornell Medical College
    Memorial Sloan Kettering Cancer Center)

  • Bülent Arman Aksoy

    (Memorial Sloan-Kettering Cancer Center
    Weill Cornell Medical College
    Medical University of South Carolina)

  • Sonali Majumdar

    (Memorial Sloan-Kettering Cancer Center)

  • Anders Jacobsen Skanderup

    (Memorial Sloan-Kettering Cancer Center
    Genome Institute of Singapore)

  • Emek Demir

    (Memorial Sloan-Kettering Cancer Center
    Computational Biology Program)

  • Nikolaus Schultz

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Chris Sander

    (Memorial Sloan-Kettering Cancer Center
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Eric C. Lai

    (Memorial Sloan-Kettering Cancer Center
    Weill Cornell Medical College)

Abstract

Somatic mutations in the RNase IIIb domain of DICER1 arise in cancer and disrupt the cleavage of 5' pre-miRNA arms. Here, we characterize an unstudied, recurrent, mutation (S1344L) in the DICER1 RNase IIIa domain in tumors from The Cancer Genome Atlas (TCGA) project and MSK-IMPACT profiling. RNase IIIa/b hotspots are absent from most cancers, but are notably enriched in uterine cancers. Systematic analysis of TCGA small RNA datasets show that DICER1 RNase IIIa-S1344L tumors deplete 5p-miRNAs, analogous to RNase IIIb hotspot samples. Structural and evolutionary coupling analyses reveal constrained proximity of RNase IIIa-S1344 to the RNase IIIb catalytic site, rationalizing why mutation of this site phenocopies known hotspot alterations. Finally, examination of DICER1 hotspot endometrial tumors reveals derepression of specific miRNA target signatures. In summary, comprehensive analyses of DICER1 somatic mutations and small RNA data reveal a mechanistic aspect of pre-miRNA processing that manifests in specific cancer settings.

Suggested Citation

  • Jeffrey Vedanayagam & Walid K. Chatila & Bülent Arman Aksoy & Sonali Majumdar & Anders Jacobsen Skanderup & Emek Demir & Nikolaus Schultz & Chris Sander & Eric C. Lai, 2019. "Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11610-1
    DOI: 10.1038/s41467-019-11610-1
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    Cited by:

    1. Trung Duc Nguyen & Tam Anh Trinh & Sheng Bao & Tuan Anh Nguyen, 2022. "Secondary structure RNA elements control the cleavage activity of DICER," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Thi Nhu-Y Le & Cong Truc Le & Tuan Anh Nguyen, 2024. "Determinants of selectivity in the dicing mechanism," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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