7plo
H. sapiens replisome-CUL2/LRR1 complex
Structural highlights
FunctionCLSPN_HUMAN Required for checkpoint mediated cell cycle arrest in response to inhibition of DNA replication or to DNA damage induced by both ionizing and UV irradiation. Adapter protein which binds to BRCA1 and the checkpoint kinase CHEK1 and facilitates the ATR-dependent phosphorylation of both proteins. Can also bind specifically to branched DNA structures and may associate with S-phase chromatin following formation of the pre-replication complex (pre-RC). This may indicate a role for this protein as a sensor which monitors the integrity of DNA replication forks.[1] [2] [3] [4] [5] 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[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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