Shout out to Sloan Kettering @mskcancercenter.bsky.social for supporting basic science / foundational biology...

www.mskcc.org/news/cryo-el...

Thanks to @dirkremus.bsky.social, Richard Hite, @benallwein.bsky.social and all the co-authors.
Thanks to @mskeducation.bsky.social, NIH, National Cancer Institute, BRIA Award @mskcancercenter.bsky.social for funding.

Unlike the bacterial hexameric ring helicases that translocate in a sequential rotary hand-over-hand mechanism, we propose CMG translocates like a 'helical inchworm', oscillating between planar and spiral states.

Importantly, the G4 traps CMG in translocation intermediate states, suggesting that CMG uses a DNA translocation mechanism that is distinct from bacterial hexameric ring helicases.

Exonuclease protection data and cryo-EM structures of the stalled CMG complexes demonstrate that the G4 is locked inside the CMG channel at the interface of the N- and C-tiers, fully folded and sequestered from G4 helicases.

We previously showed that R-loop-associated G-quadruplexes (G4s) impede replisome progression. Here, we demonstrate that a single G4 specifically in the leading strand template effectively blocks reconstituted yeast and human replisomes even in the absence of G4 stabilizers.

Thrilled to share first part of my post-doc work, published today in @science.org www.science.org/doi/10.1126/...
We use reconstituted replication system and cryo-EM to unravel an unexpected mechanism of DNA translocation employed by eukaryotic replicative helicase.