CTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere length |
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| Authors: | Peili Gu Shuting Jia Taylor Takasugi Eric Smith Jayakrishnan Nandakumar Eric Hendrickson Sandy Chang |
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| Affiliation: | 1. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut;2. Lab of Molecular Genetics of Aging and Tumor, Faculty of Medicine, Kunming University of Science and Technology, Kunming, Yunnan Province, China;3. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, Minnesota;4. Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan;5. Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan;6. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut;7. Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut |
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| 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. |
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| Keywords: | DNA repair stem cell aging telomerase telomere |
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