Shukla Siddharth, Bjerke Glen A, Muhlrad Denise, Yi Rui, Parker Roy
Department of Biochemistry, University of Colorado, Boulder, CO 80303, USA.
Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80303, USA.
Mol Cell. 2019 Mar 21;73(6):1204-1216.e4. doi: 10.1016/j.molcel.2019.01.010. Epub 2019 Feb 12.
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.
PARN功能丧失突变会导致一种严重形式的遗传性疾病先天性角化不良（DC）。PARN缺乏会影响非编码RNA的稳定性，如人端粒酶RNA（hTR），但这些影响并不能解释患者所患的严重疾病。我们证明，PARN缺乏会影响人类细胞中众多miRNA的水平。PARN通过去除由多聚腺苷酸聚合酶PAPD5添加的寡聚（A）尾巴来稳定成熟或前体miRNA，从而调节miRNA水平，如果这些尾巴保留，则会招募核酸外切酶DIS3L或DIS3L2来降解miRNA。敲低PARN会使多种抑制p53翻译的miRNA不稳定，从而导致p53以Dicer依赖的方式积累增加，这就解释了为什么PARN缺陷患者会出现p53积累。这项研究还揭示，DIS3L和DIS3L2是调节miRNA稳定性的关键3'至5'核酸外切酶，3'末端延伸的添加和去除控制着细胞内miRNA的水平。
