Molecular biology of telomeropathies. The processes required to correctly replicate and extend telomeres are outlined; genes with known disease-causing mutations are denoted in red. Telomeres are packaged in a “T-loop” configuration characterized by G-strand invasion of the centromere-proximal double-stranded DNA. The T-loop must be dissociated before replication of the telomere can take place, which is accomplished by the RTEL1 helicase. DNA replication after T-loop resolution yields blunt-ended (from leading-strand synthesis) and RNA primer–ended (from lagging strand synthesis) telomere ends, which must be processed by the CST complex (composed of CTC1, STN1, and TEN1) and Apollo before telomerase activity. Telomerase is a complex containing TERT, TERC, and a dimer of the Dyskerin complex (Dyskerin, NOP10, NHP2, GAR1), and its assembly is promoted by TCAB1 in the Cajal body. After assembly, telomerase is localized to the replicated and processed telomere by TCAB1 and TPP1, where it can add 50–100 base pairs of new telomere repeats to the G-overhang. After telomerase activity, the CST complex and DNA polymerase-α perform a fill-in reaction and nucleolytic processing that yields an extended telomere closed to further action by telomerase.