Zinc finger CCHC domain-containing protein 8
RNA binding
<i>ZCCHC8</i>, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation.
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 <i>ZCCHC8</i>, a zinc-knuckle containing protein, as a cause of autosomal dominant pulmonary fibrosis. ZCCHC8 associated with <i>TR</i> and was required for telomerase function. In ZCCHC8 knockout cells and in mutation carriers, genomically extended telomerase RNA (<i>TR</i>) accumulated at the expense of mature <i>TR</i>, consistent with a role for ZCCHC8 in mediating <i>TR</i> 3' end targeting to the nuclear RNA exosome. We generated <i>Zcchc8</i>-null mice and found that heterozygotes, similar to human mutation carriers, had <i>TR</i> insufficiency but an otherwise preserved transcriptome. In contrast, <i>Zcchc8<sup>-/-</sup></i> mice developed progressive and fatal neurodevelopmental pathology with features of a ciliopathy. The <i>Zcchc8<sup>-/-</sup></i> 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 <i>TR</i> shares with replication-dependent histones.