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ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation.
Genes & development Pub Date : 2019-09-05 , DOI: 10.1101/gad.326785.119
Dustin L Gable 1, 2, 3 , Valeriya Gaysinskaya 2, 3 , Christine C Atik 2, 3 , C Conover Talbot 4 , Byunghak Kang 5 , Susan E Stanley 1, 2, 3 , Elizabeth W Pugh 6 , Nuria Amat-Codina 2, 3 , Kara M Schenk 7 , Murat O Arcasoy 8 , Cory Brayton 5 , Liliana Florea 6 , Mary Armanios 2, 3, 6, 9
Affiliation  

Short telomere syndromes manifest as familial idiopathic pulmonary fibrosis; they are the most common premature aging disorders. We used genome-wide linkage to identify heterozygous loss of function of ZCCHC8, a zinc-knuckle containing protein, as a cause of autosomal dominant pulmonary fibrosis. ZCCHC8 associated with TR and was required for telomerase function. In ZCCHC8 knockout cells and in mutation carriers, genomically extended telomerase RNA (TR) accumulated at the expense of mature TR, consistent with a role for ZCCHC8 in mediating TR 3' end targeting to the nuclear RNA exosome. We generated Zcchc8-null mice and found that heterozygotes, similar to human mutation carriers, had TR insufficiency but an otherwise preserved transcriptome. In contrast, Zcchc8-/- mice developed progressive and fatal neurodevelopmental pathology with features of a ciliopathy. The Zcchc8-/- brain transcriptome was highly dysregulated, showing accumulation and 3' end misprocessing of other low-abundance RNAs, including those encoding cilia components as well as the intronless replication-dependent histones. Our data identify a novel cause of human short telomere syndromes-familial pulmonary fibrosis and uncover nuclear exosome targeting as an essential 3' end maturation mechanism that vertebrate TR shares with replication-dependent histones.

中文翻译:

ZCCHC8 是核外泌体靶向成分,在家族性肺纤维化中发生突变,并且是端粒酶 RNA 成熟所必需的。

短端粒综合征表现为家族性特发性肺纤维化;它们是最常见的过早衰老障碍。我们使用全基因组连锁来鉴定 ZCCHC8(一种含锌关节蛋白)的杂合子功能丧失,作为常染色体显性肺纤维化的原因。ZCCHC8 与 TR 相关,并且是端粒酶功能所必需的。在 ZCCHC8 敲除细胞和突变携带者中,基因组扩展的端粒酶 RNA (TR) 以成熟 TR 为代价积累,这与 ZCCHC8 在介导 TR 3' 末端靶向核 RNA 外泌体中的作用一致。我们生成了 Zcchc8-null 小鼠,发现杂合子与人类突变携带者相似,具有 TR 功能不全,但转录组在其他方面得到保留。相比之下,Zcchc8-/- 小鼠出现了具有纤毛病特征的进行性和致命的神经发育病理学。Zcchc8-/- 脑转录组高度失调,显示其他低丰度 RNA 的积累和 3' 末端错误加工,包括编码纤毛成分的那些以及无内含子的复制依赖组蛋白。我们的数据确定了人类短端粒综合征的新原因——家族性肺纤维化,并揭示了核外泌体靶向是脊椎动物 TR 与复制依赖组蛋白共享的一种重要的 3' 端成熟机制。
更新日期:2019-11-01
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