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


Authors: Vedanayagam, J.; Chatila, W. K.; Aksoy, B. A.; Majumdar, S.; Skanderup, A. J.; Demir, E.; Schultz, N.; Sander, C.; Lai, E. C.
Article Title: Cancer-associated mutations in DICER1 RNase IIIa and IIIb domains exert similar effects on miRNA biogenesis
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. © 2019, The Author(s).
Journal Title: Nature Communications
Volume: 10
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2019-08-15
Start Page: 3682
Language: English
DOI: 10.1038/s41467-019-11610-1
PROVIDER: scopus
PMCID: PMC6695490
PUBMED: 31417090
DOI/URL:
Notes: Article -- Export Date: 4 September 2019 -- Source: Scopus
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MSK Authors
  1. Eric C Lai
    123 Lai
  2. Chris Sander
    204 Sander
  3. Emek Demir
    27 Demir
  4. Nikolaus D Schultz
    262 Schultz
  5. Bulent Arman Aksoy
    35 Aksoy
  6. Walid Khaled Chatila
    23 Chatila