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Mol Cell 2023 Nov 16;8322:4017-4031.e9. doi: 10.1016/j.molcel.2023.09.029.
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The structural mechanism of dimeric DONSON in replicative helicase activation.

Cvetkovic MA , Passaretti P , Butryn A , Reynolds-Winczura A , Kingsley G , Skagia A , Fernandez-Cuesta C , Poovathumkadavil D , George R , Chauhan AS , Jhujh SS , Stewart GS , Gambus A , Costa A .

The MCM motor of the replicative helicase is loaded onto origin DNA as an inactive double hexamer before replication initiation. Recruitment of activators GINS and Cdc45 upon S-phase transition promotes the assembly of two active CMG helicases. Although work with yeast established the mechanism for origin activation, how CMG is formed in higher eukaryotes is poorly understood. Metazoan Downstream neighbor of Son (DONSON) has recently been shown to deliver GINS to MCM during CMG assembly. What impact this has on the MCM double hexamer is unknown. Here, we used cryoelectron microscopy (cryo-EM) on proteins isolated from replicating Xenopus egg extracts to identify a double CMG complex bridged by a DONSON dimer. We find that tethering elements mediating complex formation are essential for replication. DONSON reconfigures the MCM motors in the double CMG, and primordial dwarfism patients' mutations disrupting DONSON dimerization affect GINS and MCM engagement in human cells and DNA synthesis in Xenopus egg extracts.

PubMed ID: 37820732
Article link: Mol Cell
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: cdc45 donson gins1 gins2 gins3 gins4 mcm2 mcm3 mcm6 mcm7 mmut mtbp pcna ticrr topbp1
GO keywords: DNA helicase activity [+]
Antibodies: Cdc45 Ab2 DONSON Ab2 DONSON Ab3 FLAG Ab2 GINS Ab1 Mcm2 Ab3 Mcm7 Ab4 Pcna Ab5 Psf2 Ab1 Recql4 Ab2 ticrr Ab2

Disease Ontology terms: microcephalic osteodysplastic primordial dwarfism type II

Article Images: [+] show captions