The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres

Amanda K. Frank, Duy C. Tran, Roy W. Qu, Bradley A. Stohr, David Segal, Lifeng Xu

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Dyskeratosis Congenita (DC) is a heritable multi-system disorder caused by abnormally short telomeres. Clinically diagnosed by the mucocutaneous symptoms, DC patients are at high risk for bone marrow failure, pulmonary fibrosis, and multiple types of cancers. We have recapitulated the most common DC-causing mutation in the shelterin component TIN2 by introducing a TIN2-R282H mutation into cultured telomerase-positive human cells via a knock-in approach. The resulting heterozygous TIN2-R282H mutation does not perturb occupancy of other shelterin components on telomeres, result in activation of telomeric DNA damage signaling or exhibit other characteristics indicative of a telomere deprotection defect. Using a novel assay that monitors the frequency and extension rate of telomerase activity at individual telomeres, we show instead that telomerase elongates telomeres at a reduced frequency in TIN2-R282H heterozygous cells; this recruitment defect is further corroborated by examining the effect of this mutation on telomerase-telomere co-localization. These observations suggest a direct role for TIN2 in mediating telomere length through telomerase, separable from its role in telomere protection.

Original languageEnglish (US)
Article numbere1005410
JournalPLoS Genetics
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2015

Fingerprint

telomerase
Telomerase
telomeres
Telomere
mutation
Dyskeratosis Congenita
defect
Mutation
bone
cancer
assay
DNA
damage
Pulmonary Fibrosis
fibrosis
DNA damage
bone marrow
signs and symptoms (animals and humans)
DNA Damage
Bone Marrow

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres. / Frank, Amanda K.; Tran, Duy C.; Qu, Roy W.; Stohr, Bradley A.; Segal, David; Xu, Lifeng.

In: PLoS Genetics, Vol. 11, No. 7, e1005410, 01.07.2015.

Research output: Contribution to journalArticle

Frank, Amanda K. ; Tran, Duy C. ; Qu, Roy W. ; Stohr, Bradley A. ; Segal, David ; Xu, Lifeng. / The Shelterin TIN2 Subunit Mediates Recruitment of Telomerase to Telomeres. In: PLoS Genetics. 2015 ; Vol. 11, No. 7.
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