Structure of Tetrahymena telomerase-bound CST with polymerase α-primase

He, Yao; He, Song; Chan, Henry; Liu, Baocheng; Wang, Yaqiang; Sušac, Lukas; Zh, Zhou; Feigon, Juli

doi:10.1038/s41586-022-04931-7

Cited by 36 publications

(35 citation statements)

References 74 publications

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“…Recently, three eukaryotic model systems have shed light on this central process: The lagging strand synthesis of telomere sequences using Pol-prim and CTC1-STN1-TEN1 (CST) complex (Figure 2; N.B in mouse CTC1 and STN1 are equivalent to the AAF132 and AAF44 subunits of alpha-Accessory factor (AAF) [48]). The SV40 system using Tag, RPA plus Pol-prim, and the cellular replication system with purified yeast and human proteins have advanced our understanding [17,18,25,29,32,46,[49][50][51][52][53][54][55][56][57][58].…”

Section: Lagging Strand Synthesis and The Initiation Of Okazaki Fragm...mentioning

confidence: 99%

“…The recent publication of four-landmark articles has produced major advances in our understanding of the initiation of Okazaki fragment synthesis at telomere sequences and beyond on the mechanistic level and in general ( [17,18,49,58] reviewed in [51]). Telomere sequences consist of repetitive DNA sequences at the end of linear chromosomes of eukaryotes and form specific protein-DNA complexes, the sheltering complex, to stabilise these ends during normal cell metabolism to avoid DNA damage signalling [7,60].…”

Section: A Biochemical Model Systems For the Initiation Of Okazaki Fr...mentioning

confidence: 99%

See 1 more Smart Citation

Lagging Strand Initiation Processes in DNA Replication of Eukaryotes – Strings of Highly Coordinated Reactions Governed by Multiprotein Complexes

Nasheuer¹,

Onwubiko²

2023

Preprint

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The term ‘Hallmarks of Cancer’ was coined by Hanahan and Weinberg in their influential reviews and they described genome instability as a property of cells enabling cancer development [1, 2]. Accurate DNA replication of genomes is central to diminish genome instability. Here, the understanding of the initiation of DNA synthesis in origins of DNA replication to start leading strand synthesis and the initiation of Okazaki fragment on the lagging strand are crucial to control genome instability. Recent findings have provided new insights into the mechanism of the remodelling of the prime initiation enzyme, DNA polymerase α-primase, during primer synthesis, how the enzyme complex achieves lagging strand synthesis, and how it is linked to replication forks to achieve optimal initiation of Okazaki fragments. Moreover, the central roles of RNA primer synthesis by Pol-prim in multiple genome stability pathways such as replication fork restart and protection of DNA against degradation by exonucleases during double-strand break repair is discussed.

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Section: Lagging Strand Synthesis and The Initiation Of Okazaki Fragm...mentioning

confidence: 99%

Section: A Biochemical Model Systems For the Initiation Of Okazaki Fr...mentioning

confidence: 99%

Lagging Strand Initiation Processes in DNA Replication of Eukaryotes – Strings of Highly Coordinated Reactions Governed by Multiprotein Complexes

Nasheuer¹,

Onwubiko²

2023

Preprint

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“…We might have expected that this shelterin complex would affect CST-Polα-primase action, given that human POT1 and TPP1, as well as mouse POT1b, have been shown to bind CST 10,33 . Furthermore, a recent cryo-EM structure of Tetrahymena telomerase bound to CST-Polα-primase revealed an interaction between Tetrahymena p50 (an orthologue of human TPP1) and CST 34 . Given that we saw no impact on C-strand synthesis with stoichiometric POT1-TPP1N, it remains to be seen whether POT1-CST or TPP1-CST interactions that may occur in the human system affect C-strand synthesis.…”

Section: Articlementioning

confidence: 99%

Reconstitution of a telomeric replicon organized by CST

Zaug

Goodrich

Song

et al. 2022

Nature

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Telomeres, the natural ends of linear chromosomes, comprise repeat-sequence DNA and associated proteins1. Replication of telomeres allows continued proliferation of human stem cells and immortality of cancer cells2. This replication requires telomerase3 extension of the single-stranded DNA (ssDNA) of the telomeric G-strand ((TTAGGG)n); the synthesis of the complementary C-strand ((CCCTAA)n) is much less well characterized. The CST (CTC1–STN1–TEN1) protein complex, a DNA polymerase α-primase accessory factor4,5, is known to be required for telomere replication in vivo6–9, and the molecular analysis presented here reveals key features of its mechanism. We find that human CST uses its ssDNA-binding activity to specify the origins for telomeric C-strand synthesis by bound Polα-primase. CST-organized DNA polymerization can copy a telomeric DNA template that folds into G-quadruplex structures, but the challenges presented by this template probably contribute to telomere replication problems observed in vivo. Combining telomerase, a short telomeric ssDNA primer and CST–Polα–primase gives complete telomeric DNA replication, resulting in the same sort of ssDNA 3′ overhang found naturally on human telomeres. We conclude that the CST complex not only terminates telomerase extension10,11 and recruits Polα–primase to telomeric ssDNA4,12,13 but also orchestrates C-strand synthesis. Because replication of the telomere has features distinct from replication of the rest of the genome, targeting telomere-replication components including CST holds promise for cancer therapeutics.

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“…Two major telomere protecting complexes have been described, CST and shelterin. These were initially thought to be alternative mutually exclusive systems, but the search for homologues revealed that many eukaryotes, including humans, had both systems able to work in parallel [ 275 , 276 , 277 , 278 ]. Continuing research focused on looking for homologues of human systems across all eukaryotes, however this approach has had only partial success (reviewed in [ 279 ]).…”

Section: Telomere Proteinsmentioning

confidence: 99%

Telomeres and Their Neighbors

Jenner

Peška

Fulnečková

et al. 2022

Genes

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Telomeres are essential structures formed from satellite DNA repeats at the ends of chromosomes in most eukaryotes. Satellite DNA repeat sequences are useful markers for karyotyping, but have a more enigmatic role in the eukaryotic cell. Much work has been done to investigate the structure and arrangement of repetitive DNA elements in classical models with implications for species evolution. Still more is needed until there is a complete picture of the biological function of DNA satellite sequences, particularly when considering non-model organisms. Celebrating Gregor Mendel’s anniversary by going to the roots, this review is designed to inspire and aid new research into telomeres and satellites with a particular focus on non-model organisms and accessible experimental and in silico methods that do not require specialized equipment or expensive materials. We describe how to identify telomere (and satellite) repeats giving many examples of published (and some unpublished) data from these techniques to illustrate the principles behind the experiments. We also present advice on how to perform and analyse such experiments, including details of common pitfalls. Our examples are a selection of recent developments and underexplored areas of research from the past. As a nod to Mendel’s early work, we use many examples from plants and insects, especially as much recent work has expanded beyond the human and yeast models traditional in telomere research. We give a general introduction to the accepted knowledge of telomere and satellite systems and include references to specialized reviews for the interested reader.

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Structure of Tetrahymena telomerase-bound CST with polymerase α-primase

Cited by 36 publications

References 74 publications

Lagging Strand Initiation Processes in DNA Replication of Eukaryotes – Strings of Highly Coordinated Reactions Governed by Multiprotein Complexes

Lagging Strand Initiation Processes in DNA Replication of Eukaryotes – Strings of Highly Coordinated Reactions Governed by Multiprotein Complexes

Reconstitution of a telomeric replicon organized by CST

Telomeres and Their Neighbors

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