Let-7 miRNAs are Selectively Sensitive to Dicer Dosage

DICER1 syndrome is a rare cancer predisposition disorder linked to disruption of the miRNA biogenesis enzyme Dicer. To model germline DICER1 loss, we generated heterozygous knockout cell lines in mouse and human systems. While global miRNA levels were largely unaffected, the let-7 family was consistently downregulated across all models. The coordinated reduction of both guide and passenger strands, without similar effects on co-transcribed miRNAs, indicates a post-transcriptional biogenesis mechanism. These findings reveal a selective sensitivity of let-7 miRNAs to Dicer dosage and suggest a role for let-7 dysregulation in DICER1-associated tumorigenesis.