Moon Diane H, Segal Matthew, Boyraz Baris, Guinan Eva, Hofmann Inga, Cahan Patrick, Tai Albert K, Agarwal Suneet
Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Nat Genet. 2015 Dec;47(12):1482-8. doi: 10.1038/ng.3423. Epub 2015 Oct 19.
Mutations in the PARN gene (encoding poly(A)-specific ribonuclease) cause telomere diseases including familial idiopathic pulmonary fibrosis (IPF) and dyskeratosis congenita, but how PARN deficiency impairs telomere maintenance is unclear. Here, using somatic cells and induced pluripotent stem cells (iPSCs) from patients with dyskeratosis congenita with PARN mutations, we show that PARN is required for the 3'-end maturation of the telomerase RNA component (TERC). Patient-derived cells as well as immortalized cells in which PARN is disrupted show decreased levels of TERC. Deep sequencing of TERC RNA 3' termini shows that PARN is required for removal of post-transcriptionally acquired oligo(A) tails that target nuclear RNAs for degradation. Diminished TERC levels and the increased proportion of oligo(A) forms of TERC are normalized by restoring PARN, which is limiting for TERC maturation in cells. Our results demonstrate a new role for PARN in the biogenesis of TERC and provide a mechanism linking PARN mutations to telomere diseases.
PARN基因(编码聚腺苷酸特异性核糖核酸酶)的突变会导致端粒疾病,包括家族性特发性肺纤维化(IPF)和先天性角化不良,但PARN缺乏如何损害端粒维持尚不清楚。在这里,我们使用来自患有PARN突变的先天性角化不良患者的体细胞和诱导多能干细胞(iPSC),表明PARN是端粒酶RNA组分(TERC)3'端成熟所必需的。患者来源的细胞以及PARN被破坏的永生化细胞显示TERC水平降低。TERC RNA 3'末端的深度测序表明,PARN是去除转录后获得的寡聚(A)尾巴所必需的,这些尾巴靶向核RNA进行降解。通过恢复PARN可使TERC水平降低和TERC寡聚(A)形式比例增加的情况正常化,PARN在细胞中对TERC成熟是有限的。我们的结果证明了PARN在TERC生物合成中的新作用,并提供了一种将PARN突变与端粒疾病联系起来的机制。