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Cryo-EM structure of human CST bound to POT1(ESDL)/TPP1 in the absence of telomeric ssDNACryo-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. FunctionCTC1_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] MALE_ECO57 Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides (By similarity). Publication Abstract from PubMedCST-Polalpha/Primase maintains telomeres through fill-in synthesis of the C-rich telomeric DNA. We report cryo-EM structures that reveal how human CST is recruited to telomeres by the shelterin subunits POT1 and TPP1. CST-POT1/TPP1 is formed through interactions between POT1 and the Ctc1 subunit of CST. Coats plus syndrome mutations map to the POT1-Ctc1 interface, providing mechanistic insights into this disease. CST-POT1/TPP1 is compatible with the previously reported inactive recruitment complex of CST-Polalpha/Primase but not with the distinct conformation of active CST-Polalpha/Primase. We propose that shelterin both recruits and regulates CST-Polalpha/Primase. Structural and biochemical data indicate that this regulation involves phosphorylation of POT1, which promotes CST-POT1/TPP1 interaction and recruitment, whereas POT1 dephosphorylation releases CST-Polalpha/Primase for fill-in synthesis. ONE-SENTENCE SUMMARY: Cryo-EM structures reveal how telomere maintenance factors are recruited and regulated by the shelterin complex. Structural basis of CST-Polalpha/Primase recruitment and regulation by POT1 at telomeres.,Cai SW, Takai H, Walz T, de Lange T bioRxiv. 2023 May 9:2023.05.08.539880. doi: 10.1101/2023.05.08.539880. Preprint. PMID:37215005[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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