CTC1-STN1 coordinates G- and C-strand synthesis to regulate telomere length

Peili Gu, Shuting Jia, Taylor Takasugi, Eric Smith, Jayakrishnan Nandakumar, Eric A Hendrickson, Sandy Chang

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Coats plus (CP) is a rare autosomal recessive disorder caused by mutations in CTC1, a component of the CST (CTC1, STN1, and TEN1) complex important for telomere length maintenance. The molecular basis of how CP mutations impact upon telomere length remains unclear. The CP CTC1L1142H mutation has been previously shown to disrupt telomere maintenance. In this study, we used CRISPR/Cas9 to engineer this mutation into both alleles of HCT116 and RPE cells to demonstrate that CTC1:STN1 interaction is required to repress telomerase activity. CTC1L1142H interacts poorly with STN1, leading to telomerase-mediated telomere elongation. Impaired interaction between CTC1L1142H:STN1 and DNA Pol-α results in increased telomerase recruitment to telomeres and further telomere elongation, revealing that C:S binding to DNA Pol-α is required to fully repress telomerase activity. CP CTC1 mutants that fail to interact with DNA Pol-α resulted in loss of C-strand maintenance and catastrophic telomere shortening. Our findings place the CST complex as an important regulator of both G-strand extensions by telomerase and C-strand synthesis by DNA Pol-α.

Original languageEnglish (US)
Article numbere12783
JournalAging cell
Volume17
Issue number4
DOIs
StatePublished - Aug 2018

Bibliographical note

Funding Information:
We would like to thank the Chang lab for helpful suggestions and to Yinan Kan for helpful advice. This work was supported by the NCI (RO1 CA129037, RO1CA202816, R21CA200506 and R21CA182280 to S.C.), the NIH (R00CA167644, R01GM120094, R01AG050509 to J.N.), the American Cancer Society Research Scholar grant (RSG-17-037-01-DMC to J.N.), the NIH Biology of Aging Training Grant (T32AG000114) awarded to the University of Michigan Geriatrics Center from the National Institute on Aging (fellowship to E.M.S.).

Funding Information:
NCI, Grant/Award Number: RO1 CA129037, RO1CA202816, R21CA200506, R21CA182280; NIH, Grant/Award Number: R00CA167644, R01GM120094, R01AG050509; American Cancer Society Research Scholar, Grant/Award Number: RSG-17-037-01-DMC; NIH Biology of Aging Training Grant, Grant/Award Number: T32AG000114

Keywords

  • DNA repair
  • stem cell aging
  • telomerase
  • telomere

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