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Instruments / Technical Area	Publication Details	Published
I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	Structural basis for inhibition of human primase by arabinofuranosyl nucleoside analogues fludarabine and vidarabine Sandro Holzer , Neil J. Rzechorzek , Isobel R. Short , Michael Jenkyn-Bedford , Luca Pellegrini , Mairi Kilkenny Acs Chemical Biology DOI: 10.1021/acschembio.9b00367 Diamond Proposal Number(s): [9537] Open Access Show Abstract ▼ Abstract: Nucleoside analogues are widely used in clinical practice as chemotherapy drugs. Arabinose nucleoside derivatives such as fludarabine are effective in the treatment of patients with acute and chronic leukemias and non-Hodgkin lymphomas. Although nucleoside analogues are generally known to function by inhibiting DNA synthesis in rapidly proliferating cells, the identity of their in vivo targets and mechanism of action are often not known in molecular detail. Here we provide a structural basis for arabinose nucleotide-mediated inhibition of human primase, the DNA-dependent RNA polymerase responsible for initiation of DNA synthesis in DNA replication. Our data suggest ways in which the chemical structure of fludarabine could be modified to improve its specificity and affinity towards primase, possibly leading to less toxic and more effective therapeutic agents.	Sep 2019
Krios I-Titan Krios I at Diamond	Cryo-EM structure of the fork protection complex bound to CMG at a replication fork Domagoj Baretic , Michael Jenkyn-Bedford , Valentina Aria , Giuseppe Cannone , Mark Skehel , Joseph T. P. Yeeles Molecular Cell 78, 926 - 940.e13 DOI: 10.1016/j.molcel.2020.04.012 Diamond Proposal Number(s): [20976, 17434] Open Access Show Abstract ▼ Abstract: The eukaryotic replisome, organized around the Cdc45-MCM-GINS (CMG) helicase, orchestrates chromosome replication. Multiple factors associate directly with CMG, including Ctf4 and the heterotrimeric fork protection complex (Csm3/Tof1 and Mrc1), which has important roles including aiding normal replication rates and stabilizing stalled forks. How these proteins interface with CMG to execute these functions is poorly understood. Here we present 3 to 3.5 Å resolution electron cryomicroscopy (cryo-EM) structures comprising CMG, Ctf4, and the fork protection complex at a replication fork. The structures provide high-resolution views of CMG-DNA interactions, revealing a mechanism for strand separation, and show Csm3/Tof1 “grip” duplex DNA ahead of CMG via a network of interactions important for efficient replication fork pausing. Although Mrc1 was not resolved in our structures, we determine its topology in the replisome by cross-linking mass spectrometry. Collectively, our work reveals how four highly conserved replisome components collaborate with CMG to facilitate replisome progression and maintain genome stability.	Jun 2020
Krios IV-Titan Krios IV at Diamond	A conserved mechanism for regulating replisome disassembly in eukaryotes Michael Jenkyn-Bedford , Morgan L. Jones , Yasemin Baris , Karim P. M. Labib , Giuseppe Cannone , Joseph T. P. Yeeles , Tom D. Deegan Nature 600, 743 - 747 DOI: 10.1038/s41586-021-04145-3 Diamond Proposal Number(s): [23268, 24557] Open Access Show Abstract ▼ Abstract: Replisome disassembly is the final step of eukaryotic DNA replication and is triggered by ubiquitylation of the CDC45–MCM–GINS (CMG) replicative helicase. Despite being driven by evolutionarily diverse E3 ubiquitin ligases in different eukaryotes (SCFDia2 in budding yeast1, CUL2LRR1 in metazoa), 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. However, it is unknown how SCFDia2 and CUL2LRR1 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.	Oct 2021

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