Conserved Telomere Maintenance Component 1 Interacts with STN1 and Maintains Chromosome Ends in Higher Eukaryotes

Abstract

Summary Orthologs of the yeast telomere protein Stn1 are present in plants, but other components of the Cdc13/Stn1/Ten1 (CST) complex have only been found in fungi. Here we report the identification of Conserved Telomere maintenance Component 1 (CTC1) in plants and vertebrates. CTC1 encodes an ∼140 kDa telomere-associated protein predicted to contain multiple OB-fold domains. Arabidopsis mutants null for CTC1 display a severe telomere deprotection phenotype accompanied by a rapid onset of developmental defects and sterility. Telomeric and subtelomeric tracts are dramatically eroded, and chromosome ends exhibit increased G-overhangs, recombination, and end-to-end fusions. AtCTC1 both physically and genetically interacts with AtSTN1. Depletion of human CTC1 by RNAi triggers a DNA damage response, chromatin bridges, increased G-overhangs and sporadic telomere loss. These data indicate that CTC1 participates in telomere maintenance in diverse species and that a CST-like complex is required for telomere integrity in multicellular organisms.

Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus

“…Recently, it has been shown that CTC1 interacts with STN1 and TEN1 to form the mammalian homolog of the yeast hetero trimeric Cdc13 Stn1 Ten1 (CST) telomeric capping complex 13,14 . Consequently, we also undertook Sanger sequencing of OBFC1 (STN1) and TEN1 in our collection of individuals with Labrune syndrome and in the proband with Coats plus in whom we identified no CTC1 mutations.…”

“…In view of the finding of shortened telomeres in an Arabidopsis CTC1 mutant 13 and the phenotypic overlap between Coats plus and the telomeric maintenance disorders comprising dyskeratosis con genita, we measured telomere lengths 15 in F332, F367 and F382 at the ages of 20, 20 and 3 years, respectively. Samples were also available from the mother and heterozygous brother of F367 and from both parents of F332 and F382.…”

“…Because of rapid evolutionary divergence, the human CST complex was only defined recently 13,14 . This led to the recognition that mammalian l e t t e r s CTC1 is identical to one subunit of α accessory factor (AAF 132), whereas a second subunit of AAF (AAF 44, also known as OBFC1) corresponds to mammalian STN1 (ref.…”

“…However, the CST complex only partially localizes to telomeres and binds to ssDNA in a sequence independent manner (through the oligonucleotide/oligosaccharide binding (OB) fold domains predicted to be present in all three subunits) 13,14 . Of note, knockdown of CTC1 in human cells resulted in an increase in the number of γH2AX foci not confined to telomeres 13 .…”

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

“…These proteins include the evolutionarily conserved CTC1: STN1: TEN1 (CST) complex. CTC1 and STN1 were originally discovered as proteins that stimulate DNA Pol‐α: primase activity, suggesting an essential role for CST in DNA replication (Casteel et al., 2009; Miyake et al., 2009; Surovtseva et al., 2009). Targeted deletion of CTC1 in the mouse, as well as depletion of individual CST components in human cells, all results in telomere replication defects and global telomere attrition, suggesting that the CST complex is required for multiple steps of telomere replication (Feng, Hsu, Kasbek, Chaiken & Price, 2017; Gu et al., 2012; Wu, Takai & de Lange, 2012).…”