Structures of the human CST-Polα–primase complex bound to telomere templates

Qixiang He, Xiuhua Lin, Bianca L. Chavez, Sourav Agrawal, Benjamin L. Lusk and Ci Ji Lim ()
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Qixiang He: University of Wisconsin–Madison
Xiuhua Lin: University of Wisconsin–Madison
Bianca L. Chavez: University of Wisconsin–Madison
Sourav Agrawal: University of Wisconsin–Madison
Benjamin L. Lusk: University of Wisconsin–Madison
Ci Ji Lim: University of Wisconsin–Madison

Nature, 2022, vol. 608, issue 7924, 826-832

Abstract: Abstract The mammalian DNA polymerase-α–primase (Polα–primase) complex is essential for DNA metabolism, providing the de novo RNA–DNA primer for several DNA replication pathways1–4 such as lagging-strand synthesis and telomere C-strand fill-in. The physical mechanism underlying how Polα–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 Polα–primase, physically organizes the enzyme for efficient primer synthesis. Cryogenic electron microscopy structures of the CST-Polα–primase preinitiation complex (PIC) bound to various types of telomere overhang reveal that template-bound CST partitions the DNA and RNA catalytic centres of Polα–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 Polα–primase. Several insights into the template-binding specificity of CST, template requirement for assembly of the CST-Polα–primase PIC and activation are also revealed in this study.

Date: 2022
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DOI: 10.1038/s41586-022-05040-1

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