DNA replication is a highly coordinated process essential for genomic stability, facilitated by complex molecular machinery known as replisomes. Central to this process is the CMG helicase (Cdc45-MCM-GINS), which unwinds DNA strands for replication. However, non-canonical DNA structures such as G-quadruplexes (G4s) present significant challenges by impeding the progression of the replication fork. A recent study by groups of Richard K. Hite and Dirk Remus, at Memorial Sloan Kettering Cancer Center, published in Science, sheds light on how G4s obstruct DNA replication and reveals a novel inchworm-like mechanism of DNA translocation by the CMG helicase.
Key Findings
The researchers employed cryo-electron microscopy (cryo-EM) to analyze the structural dynamics of yeast and human CMG helicases stalled at G4 structures. They discovered that:
- A single G4 structure can arrest DNA replication by stalling the CMG helicase’s translocation cycle.
- The G4 remains fully folded within the central channel of CMG, preventing access to specialized helicases that usually resolve such structures.
- Two distinct structural conformations of G4-stalled CMG were identified. One closely resembles CMG bound to regular replication forks, while the second reveals a previously unknown intermediate state in the translocation cycle.
- Unlike bacterial helicases that rotate in a sequential manner, CMG employs an oscillatory motion through spiral-to-planar transitions of DNA-binding loops inside its channel, resembling an “inchworm” movement.
Significance and Implications
This study provides fundamental insights into how DNA secondary structures like G4s pose formidable obstacles to genome replication, leading to replication stress. Understanding this unique inchworm-like translocation mechanism of CMG offers crucial information about genome stability maintenance and could inform therapeutic strategies targeting replication-associated disorders. Future research will focus on elucidating the kinetic aspects of this process and identifying potential mechanisms for G4-induced fork restart.
Conclusion
By uncovering how G4s stall DNA replication and how CMG adapts through a previously unrecognized translocation mechanism, Batra et al.’s findings contribute to our broader understanding of chromosomal DNA replication dynamics. These insights pave the way for future studies on resolving replication stress and ensuring faithful genome propagation.
References
Batra, S., et al. (2024). G-quadruplex–stalled eukaryotic replisome structure reveals helical inchworm DNA translocation. Science. 7 Mar 2025, Vol 387, Issue 6738. https://www.science.org/doi/10.1126/science.adt1978
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