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Cryo-EM structure of human CST bound to POT1(ESDL)/TPP1 in the absence of telomeric ssDNA
Structural highlights
DiseaseCTC1_HUMAN Coats plus syndrome;Dyskeratosis congenita. The disease is caused by mutations affecting the gene represented in this entry. FunctionMALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.CTC1_HUMAN Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity by themselves. Initially the CST complex has been proposed to protect telomeres from DNA degradation (PubMed:19854130). However, the CST complex has been shown to be involved in several aspects of telomere replication. The CST complex inhibits telomerase and is involved in telomere length homeostasis; it is proposed to bind to newly telomerase-synthesized 3' overhangs and to terminate telomerase action implicating the association with the ACD:POT1 complex thus interfering with its telomerase stimulation activity. The CST complex is also proposed to be involved in fill-in synthesis of the telomeric C-strand probably implicating recruitment and activation of DNA polymerase alpha (PubMed:22763445). The CST complex facilitates recovery from many forms of exogenous DNA damage; seems to be involved in the re-initiation of DNA replication at repaired forks and/or dormant origins (PubMed:25483097). Involved in telomere maintenance (PubMed:19854131, PubMed:22863775). Involved in genome stability (PubMed:22863775). May be in involved in telomeric C-strand fill-in during late S/G2 phase (By similarity).[UniProtKB:Q5SUQ9][1] [2] [3] [4] [5] Publication Abstract from PubMedTelomere maintenance requires the extension of the G-rich telomeric repeat strand by telomerase and the fill-in synthesis of the C-rich strand by Polalpha/primase. At telomeres, Polalpha/primase is bound to Ctc1/Stn1/Ten1 (CST), a single-stranded DNA-binding complex. Like mutations in telomerase, mutations affecting CST-Polalpha/primase result in pathological telomere shortening and cause a telomere biology disorder, Coats plus (CP). We determined cryogenic electron microscopy structures of human CST bound to the shelterin heterodimer POT1/TPP1 that reveal how CST is recruited to telomeres by POT1. Our findings suggest that POT1 hinge phosphorylation is required for CST recruitment, and the complex is formed through conserved interactions involving several residues mutated in CP. Our structural and biochemical data suggest that phosphorylated POT1 holds CST-Polalpha/primase in an inactive, autoinhibited state until telomerase has extended the telomere ends. We propose that dephosphorylation of POT1 releases CST-Polalpha/primase into an active state that completes telomere replication through fill-in synthesis. POT1 recruits and regulates CST-Polalpha/primase at human telomeres.,Cai SW, Takai H, Zaug AJ, Dilgen TC, Cech TR, Walz T, de Lange T Cell. 2024 Jul 11;187(14):3638-3651.e18. doi: 10.1016/j.cell.2024.05.002. Epub , 2024 Jun 4. PMID:38838667[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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