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

Jeffrey Vedanayagam, Walid K. Chatila, Bülent Arman Aksoy, Sonali Majumdar, Anders Jacobsen Skanderup, Emek Demir, Nikolaus Schultz, Chris Sander () and Eric C. Lai ()
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Jeffrey Vedanayagam: Memorial Sloan-Kettering Cancer Center
Walid K. Chatila: Memorial Sloan-Kettering Cancer Center
Bülent Arman Aksoy: Memorial Sloan-Kettering Cancer Center
Sonali Majumdar: Memorial Sloan-Kettering Cancer Center
Anders Jacobsen Skanderup: Memorial Sloan-Kettering Cancer Center
Emek Demir: Memorial Sloan-Kettering Cancer Center
Nikolaus Schultz: Memorial Sloan Kettering Cancer Center
Chris Sander: Memorial Sloan-Kettering Cancer Center
Eric C. Lai: Memorial Sloan-Kettering Cancer Center

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11610-1

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