Open AccessCTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere length
Author(s) -
Gu Peili,
Jia Shuting,
Takasugi Taylor,
Smith Eric,
Nandakumar Jayakrishnan,
Hendrickson Eric,
Chang Sandy
Publication year - 2018
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12783
Subject(s) - telomere , telomerase , biology , telomere binding protein , dna , mutation , telomerase rna component , mutant , genetics , microbiology and biotechnology , cas9 , crispr , telomerase reverse transcriptase , dna binding protein , gene , transcription factor
Summary Coats plus ( CP ) is a rare autosomal recessive disorder caused by mutations in CTC 1, a component of the CST ( CTC 1, STN 1, and TEN 1) complex important for telomere length maintenance. The molecular basis of how CP mutations impact upon telomere length remains unclear. The CP CTC 1 L1142H mutation has been previously shown to disrupt telomere maintenance. In this study, we used CRISPR /Cas9 to engineer this mutation into both alleles of HCT 116 and RPE cells to demonstrate that CTC 1: STN 1 interaction is required to repress telomerase activity. CTC 1 L1142H interacts poorly with STN 1, leading to telomerase‐mediated telomere elongation. Impaired interaction between CTC 1 L1142H : STN 1 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 CTC 1 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.