7pmk | pdb_00007pmk
S. cerevisiae replisome-SCF(Dia2) complex bound to double-stranded DNA (conformation I)
Structural highlights
FunctionMCM3_YEAST Acts as component of the MCM2-7 complex (MCM complex) which is the putative replicative helicase essential for 'once per cell cycle' DNA replication initiation and elongation in eukaryotic cells. The active ATPase sites in the MCM2-7 ring are formed through the interaction surfaces of two neighboring subunits such that a critical structure of a conserved arginine finger motif is provided in trans relative to the ATP-binding site of the Walker A box of the adjacent subunit. The six ATPase active sites, however, are likely to contribute differentially to the complex helicase activity. Once loaded onto DNA, double hexamers can slide on dsDNA in the absence of ATPase activity. Necessary for cell growth.[1] [2] Publication Abstract from PubMedReplisome disassembly is the final step of eukaryotic DNA replication and is triggered by ubiquitylation of the CDC45-MCM-GINS (CMG) replicative helicase(1-3). Despite being driven by evolutionarily diverse E3 ubiquitin ligases in different eukaryotes (SCF(Dia2) in budding yeast(1), CUL2(LRR1) in metazoa(4-7)), replisome disassembly is governed by a common regulatory principle, in which ubiquitylation of CMG is suppressed before replication termination, to prevent replication fork collapse. Recent evidence suggests that this suppression is mediated by replication fork DNA(8-10). However, it is unknown how SCF(Dia2) and CUL2(LRR1) discriminate terminated from elongating replisomes, to selectively ubiquitylate CMG only after termination. Here we used cryo-electron microscopy to solve high-resolution structures of budding yeast and human replisome-E3 ligase assemblies. Our structures show that the leucine-rich repeat domains of Dia2 and LRR1 are structurally distinct, but bind to a common site on CMG, including the MCM3 and MCM5 zinc-finger domains. The LRR-MCM interaction is essential for replisome disassembly and, crucially, is occluded by the excluded DNA strand at replication forks, establishing the structural basis for the suppression of CMG ubiquitylation before termination. Our results elucidate a conserved mechanism for the regulation of replisome disassembly in eukaryotes, and reveal a previously unanticipated role for DNA in preserving replisome integrity. A conserved mechanism for regulating replisome disassembly in eukaryotes.,Jenkyn-Bedford M, Jones ML, Baris Y, Labib KPM, Cannone G, Yeeles JTP, Deegan TD Nature. 2021 Dec;600(7890):743-747. doi: 10.1038/s41586-021-04145-3. Epub 2021 , Oct 26. PMID:34700328[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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