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 |