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

Dustin L. Gable, Valeriya Gaysinskaya, Christine C. Atik, C. Conover Talbot, Byunghak Kang, Susan E. Stanley, Elizabeth W. Pugh, Nuria Amat-Codina, Kara M. Schenk, Murat O. Arcasoy, Cory Brayton, Liliana D Florea, Mary Armanios

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1381-1396
Number of pages16
JournalGenes and Development
Volume33
Issue number19-20
DOIs
StatePublished - Oct 1 2019

Fingerprint

Exosomes
Pulmonary Fibrosis
Lung Diseases
Telomere
Licensure
Transcriptome
Histones
Exosome Multienzyme Ribonuclease Complex
Premature Aging
Nuclear RNA
Idiopathic Pulmonary Fibrosis
Mutation
Cilia
Telomerase
Heterozygote
Vertebrates
telomerase RNA
Ciliopathies
Zinc
Genome

Keywords

  • Ciliopathy
  • Lung disease
  • Nuclear RNA exosome
  • RNA processing
  • Telomerase RNA

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation. / Gable, Dustin L.; Gaysinskaya, Valeriya; Atik, Christine C.; Conover Talbot, C.; Kang, Byunghak; Stanley, Susan E.; Pugh, Elizabeth W.; Amat-Codina, Nuria; Schenk, Kara M.; Arcasoy, Murat O.; Brayton, Cory; Florea, Liliana D; Armanios, Mary.

In: Genes and Development, Vol. 33, No. 19-20, 01.10.2019, p. 1381-1396.

Research output: Contribution to journalArticle

Gable, DL, Gaysinskaya, V, Atik, CC, Conover Talbot, C, Kang, B, Stanley, SE, Pugh, EW, Amat-Codina, N, Schenk, KM, Arcasoy, MO, Brayton, C, Florea, LD & Armanios, M 2019, 'ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation', Genes and Development, vol. 33, no. 19-20, pp. 1381-1396. https://doi.org/10.1101/gad.326785.119
Gable, Dustin L. ; Gaysinskaya, Valeriya ; Atik, Christine C. ; Conover Talbot, C. ; Kang, Byunghak ; Stanley, Susan E. ; Pugh, Elizabeth W. ; Amat-Codina, Nuria ; Schenk, Kara M. ; Arcasoy, Murat O. ; Brayton, Cory ; Florea, Liliana D ; Armanios, Mary. / ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation. In: Genes and Development. 2019 ; Vol. 33, No. 19-20. pp. 1381-1396.
@article{1917d12a15df42d2a35c33b119c2c149,
title = "ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation",
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 = "Ciliopathy, Lung disease, Nuclear RNA exosome, RNA processing, Telomerase RNA",
author = "Gable, {Dustin L.} and Valeriya Gaysinskaya and Atik, {Christine C.} and {Conover Talbot}, C. and Byunghak Kang and Stanley, {Susan E.} and Pugh, {Elizabeth W.} and Nuria Amat-Codina and Schenk, {Kara M.} and Arcasoy, {Murat O.} and Cory Brayton and Florea, {Liliana D} and Mary Armanios",
year = "2019",
month = "10",
day = "1",
doi = "10.1101/gad.326785.119",
language = "English (US)",
volume = "33",
pages = "1381--1396",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "19-20",

}

TY - JOUR

T1 - ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation

AU - Gable, Dustin L.

AU - Gaysinskaya, Valeriya

AU - Atik, Christine C.

AU - Conover Talbot, C.

AU - Kang, Byunghak

AU - Stanley, Susan E.

AU - Pugh, Elizabeth W.

AU - Amat-Codina, Nuria

AU - Schenk, Kara M.

AU - Arcasoy, Murat O.

AU - Brayton, Cory

AU - Florea, Liliana D

AU - Armanios, Mary

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

KW - Ciliopathy

KW - Lung disease

KW - Nuclear RNA exosome

KW - RNA processing

KW - Telomerase RNA

UR - http://www.scopus.com/inward/record.url?scp=85072849204&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072849204&partnerID=8YFLogxK

U2 - 10.1101/gad.326785.119

DO - 10.1101/gad.326785.119

M3 - Article

C2 - 31488579

AN - SCOPUS:85072849204

VL - 33

SP - 1381

EP - 1396

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 19-20

ER -