Impaired telomere integrity and rRNA biogenesis in PARN-deficient patients and knock-out models
Impaired telomere integrity and rRNA biogenesis in PARN-deficient patients and knock-out models
复制标题
DOI：
10.15252/emmm.201810201
复制
发表时间：
2019-07-01
影响因子：
11.1
通讯作者：
Revy, Patrick
中科院分区：
文献类型：
--
作者：
Benyelles, Maname;Episkopou, Harikleia;Revy, Patrick
PARN，聚(A)特异性核糖核酸酶，调节mrna的周转和端粒酶hTR RNA组分的成熟和稳定。双等位基因PARN突变与Hoyeraal-Hreidarsson （HH）综合征有关，这是一种罕见的端粒生物学疾病，由于其严重程度，可能不仅仅是由于hTR下调所致。PARN缺乏是否影响端粒相关基因的表达尚不清楚。研究人员利用两个不相关的携带新型PARN突变的HH个体和一个具有诱导PARN互补的人类PARN敲除（KO）细胞系的细胞，发现PARN缺乏会影响端粒长度和稳定性，并下调TRF1、TRF2、TPP1、RAP1和POT1保护蛋白转录本的表达。在parn缺陷细胞中，也观察到编码dyskerin的DKC1 mRNA下调，并发现这是p53激活的结果。我们进一步发现，PARN缺乏损害了患者成纤维细胞和杂合PARN KO小鼠细胞的核糖体RNA生物发生。然而，纯合子Parn - KO导致了p53 - KO无法克服的早期胚胎致死性。我们的结果完善了我们对PARN缺乏的多效性细胞后果的认识。
PARN, poly(A)-specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Hoyeraal-Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down-regulation. Whether PARN deficiency was affecting the expression of telomere-related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock-out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down-regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down-regulation of dyskerin-encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN-deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.