The RNase PARN Controls the Levels of Specific miRNAs that Contribute to p53 Regulation

PARN loss-of-function mutations cause a severe form of the hereditary disease dyskeratosis congenita (DC). PARN deficiency affects the stability of non-coding RNAs such as human telomerase RNA (hTR), but these effects do not explain the severe disease in patients. We demonstrate that PARN deficiency affects the levels of numerous miRNAs in human cells. PARN regulates miRNA levels by stabilizing either mature or precursor miRNAs by removing oligo(A) tails added by the poly(A) polymerase PAPD5, which if remaining recruit the exonuclease DIS3L or DIS3L2 to degrade the miRNA. PARN knockdown destabilizes multiple miRNAs that repress p53 translation, which leads to an increase in p53 accumulation in a Dicer-dependent manner, thus explaining why PARN-defective patients show p53 accumulation. This work also reveals that DIS3L and DIS3L2 are critical 3′ to 5′ exonucleases that regulate miRNA stability, with the addition and removal of 3′ end extensions controlling miRNA levels in the cell. LOF mutations in the 3′ to 5′ exoribonuclease PARN lead to a severe form of dyskeratosis congenita (DC). Shukla et al. found that PARN regulates the levels of specific miRNAs in the cell that modulate p53 protein levels. PARN inhibition increases p53 levels in cancer cells, providing a therapeutic opportunity.