title: Molecular basis of telomere syndrome caused by CTC1 mutations.
abstract: Mutations in CTC1 lead to the telomere syndromes Coats Plus and dyskeratosis congenita (DC), but the molecular mechanisms involved remain unknown. CTC1 forms with STN1 and TEN1 a trimeric complex termed CST, which binds ssDNA, promotes telomere DNA synthesis, and inhibits telomerase-mediated telomere elongation. Here we identify CTC1 disease mutations that disrupt CST complex formation, the physical interaction with DNA polymerase α-primase (polα-primase), telomeric ssDNA binding in vitro, accumulation in the nucleus, and/or telomere association in vivo. While having diverse molecular defects, CTC1 mutations commonly lead to the accumulation of internal single-stranded gaps of telomeric DNA, suggesting telomere DNA replication defects as a primary cause of the disease. Strikingly, mutations in CTC1 may also unleash telomerase repression and telomere length control. Hence, the telomere defect initiated by CTC1 mutations is distinct from the telomerase insufficiencies seen in classical forms of telomere syndromes, which cause short telomeres due to reduced maintenance of distal telomeric ends by telomerase. Our analysis provides molecular evidence that CST collaborates with DNA polα-primase to promote faithful telomere DNA replication.
authors.affiliation: Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
authors.forename: Liuh-Yow
authors.initials: LY
authors.lastname: Chen
authors.forename: Jana
authors.initials: J
authors.lastname: Majerská
authors.forename: Joachim
authors.initials: J
authors.lastname: Lingner
mesh_terms: D001259:Ataxia / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics; D002114:Calcinosis / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D020863:Central Nervous System Cysts / Q000235:genetics; D019871:Dyskeratosis Congenita / Q000235:genetics; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics; D009128:Muscle Spasticity / Q000235:genetics; D009154:Mutation; D012164:Retinal Diseases / Q000235:genetics; D012640:Seizures / Q000235:genetics; D013577:Syndrome; D016615:Telomere / Q000235:genetics* / Q000378:metabolism*; D059505:Telomere Homeostasis / Q000235:genetics; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D014404:Tubulin / Q000235:genetics
chemical_list: C544945:Ctc1 protein, human; C544946:Stn1 protein, human; D034501:Telomere-Binding Proteins; D014404:Tubulin
keywords: CST complex; Coats Plus; DNA polymerase α-primase; dyskeratosis congenita; telomere syndrome