G-quadruplex-stalled eukaryotic replisome structure reveals helical inchworm DNA translocation Journal Article


Authors: Batra, S.; Allwein, B.; Kumar, C.; Devbhandari, S.; Brùˆning, J. G.; Bahng, S.; Lee, C. M.; Marians, K. J.; Hite, R. K.; Remus, D.
Article Title: G-quadruplex-stalled eukaryotic replisome structure reveals helical inchworm DNA translocation
Abstract: DNA G-quadruplexes (G4s) are non-B-form DNA secondary structures that threaten genome stability by impeding DNA replication. To elucidate how G4s induce replication fork arrest, we characterized fork collisions with preformed G4s in the parental DNA using reconstituted yeast and human replisomes. We demonstrate that a single G4 in the leading strand template is sufficient to stall replisomes by arresting the CMG helicase. Cryo-electron microscopy structures of stalled yeast and human CMG complexes reveal that the folded G4 is lodged inside the central CMG channel, arresting translocation. The G4 stabilizes the CMG at distinct translocation intermediates, suggesting an unprecedented helical inchworm mechanism for DNA translocation. These findings illuminate the eukaryotic replication fork mechanism under normal and perturbed conditions.
Keywords: genetics; dna replication; metabolism; chemistry; dna; saccharomyces cerevisiae; saccharomyces cerevisiae proteins; saccharomyces cerevisiae protein; conformation; nucleic acid conformation; dna helicases; dna helicase; g-quadruplexes; guanine quadruplex; cryoelectron microscopy; humans; human
Journal Title: Science
Volume: 387
Issue: 6738
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2025-03-07
Start Page: eadt1978
Language: English
DOI: 10.1126/science.adt1978
PUBMED: 40048517
PROVIDER: scopus
DOI/URL:
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Dirk Remus and Richard K. Hite -- Source: Scopus
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MSK Authors
  1. Kenneth Marians
    138 Marians
  2. Dirk Remus
    21 Remus
  3. Soon Bahng
    12 Bahng
  4. Chong Lee
    7 Lee
  5. Charanya   Kumar
    8 Kumar
  6. Sahil Batra
    3 Batra