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Genes Dev. 2019 Oct 1;33(19-20):1381-1396. doi: 10.1101/gad.326785.119. Epub 2019 Sep 5.

ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation.

Author information

1
Medical Scientist Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
2
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
3
Telomere Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
4
Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
5
Department of Comparative and Molecular Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
6
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
7
Osler Medical Housestaff Training Program, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
8
Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27708, USA.
9
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.

Abstract

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.

KEYWORDS:

RNA processing; ciliopathy; lung disease; nuclear RNA exosome; telomerase RNA

PMID:
31488579
DOI:
10.1101/gad.326785.119
Free PMC Article

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