Skip to main content
construction release_alert
Scholars@Duke will be undergoing maintenance April 11-15. Some features may be unavailable during this time.
cancel

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

Publication ,  Journal Article
Gable, DL; Gaysinskaya, V; Atik, CC; Talbot, CC; Kang, B; Stanley, SE; Pugh, EW; Amat-Codina, N; Schenk, KM; Arcasoy, MO; Brayton, C ...
Published in: Genes Dev
October 1, 2019

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Genes Dev

DOI

EISSN

1549-5477

Publication Date

October 1, 2019

Volume

33

Issue

19-20

Start / End Page

1381 / 1396

Location

United States

Related Subject Headings

  • Telomere Shortening
  • Telomerase
  • RNA Processing, Post-Transcriptional
  • RNA
  • Pedigree
  • Nuclear Proteins
  • Neurodevelopmental Disorders
  • Mice, Knockout
  • Mice
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Gable, D. L., Gaysinskaya, V., Atik, C. C., Talbot, C. C., Kang, B., Stanley, S. E., … Armanios, M. (2019). ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation. Genes Dev, 33(19–20), 1381–1396. https://doi.org/10.1101/gad.326785.119
Gable, Dustin L., Valeriya Gaysinskaya, Christine C. Atik, C Conover Talbot, Byunghak Kang, Susan E. Stanley, Elizabeth W. Pugh, et al. “ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation.Genes Dev 33, no. 19–20 (October 1, 2019): 1381–96. https://doi.org/10.1101/gad.326785.119.
Gable DL, Gaysinskaya V, Atik CC, Talbot CC, Kang B, Stanley SE, et al. ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation. Genes Dev. 2019 Oct 1;33(19–20):1381–96.
Gable, Dustin L., et al. “ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation.Genes Dev, vol. 33, no. 19–20, Oct. 2019, pp. 1381–96. Pubmed, doi:10.1101/gad.326785.119.
Gable DL, Gaysinskaya V, Atik CC, Talbot CC, Kang B, Stanley SE, Pugh EW, Amat-Codina N, Schenk KM, Arcasoy MO, Brayton C, Florea L, Armanios M. ZCCHC8, the nuclear exosome targeting component, is mutated in familial pulmonary fibrosis and is required for telomerase RNA maturation. Genes Dev. 2019 Oct 1;33(19–20):1381–1396.

Published In

Genes Dev

DOI

EISSN

1549-5477

Publication Date

October 1, 2019

Volume

33

Issue

19-20

Start / End Page

1381 / 1396

Location

United States

Related Subject Headings

  • Telomere Shortening
  • Telomerase
  • RNA Processing, Post-Transcriptional
  • RNA
  • Pedigree
  • Nuclear Proteins
  • Neurodevelopmental Disorders
  • Mice, Knockout
  • Mice
  • Male