8d0b | pdb_00008d0b
Human CST-DNA polymerase alpha/primase preinitiation complex bound to 4xTEL-foldback template
Structural highlights
Disease[CTC1_HUMAN] Coats plus syndrome;Dyskeratosis congenita. The disease is caused by mutations affecting the gene represented in this entry. Function[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 PubMedThe mammalian DNA polymerase-alpha-primase (Polalpha-primase) complex is essential for DNA metabolism, providing the de novo RNA-DNA primer for several DNA replication pathways(1-4) such as lagging-strand synthesis and telomere C-strand fill-in. The physical mechanism underlying how Polalpha-primase, alone or in partnership with accessory proteins, performs its complicated multistep primer synthesis function is unknown. Here we show that CST, a single-stranded DNA-binding accessory protein complex for Polalpha-primase, physically organizes the enzyme for efficient primer synthesis. Cryogenic electron microscopy structures of the CST-Polalpha-primase preinitiation complex (PIC) bound to various types of telomere overhang reveal that template-bound CST partitions the DNA and RNA catalytic centres of Polalpha-primase into two separate domains and effectively arranges them in RNA-DNA synthesis order. The architecture of the PIC provides a single solution for the multiple structural requirements for the synthesis of RNA-DNA primers by Polalpha-primase. Several insights into the template-binding specificity of CST, template requirement for assembly of the CST-Polalpha-primase PIC and activation are also revealed in this study. Structures of the human CST-Polalpha-primase complex bound to telomere templates.,He Q, Lin X, Chavez BL, Agrawal S, Lusk BL, Lim CJ Nature. 2022 Aug;608(7924):826-832. doi: 10.1038/s41586-022-05040-1. Epub 2022, Jul 13. PMID:35830881[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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