Characterizing Replisome Disassembly in Human Cells

Overview

Journal iScience

Publisher Cell Press

Date 2024 Jul 26

PMID 39055910

Authors

Rebecca M Jones

Joaquin Herrero Ruiz

Shaun Scaramuzza

Sarmi Nath

Chaoyu Liu

Marta Henklewska

Toyoaki Natsume

Robert G Bristow

Francisco Romero

Masato T Kanemaki

Agnieszka Gambus

Affiliations

Soon will be listed here.

Abstract

To ensure timely duplication of the entire eukaryotic genome, thousands of replication machineries (replisomes) act on genomic DNA at any time during S phase. In the final stages of this process, replisomes are unloaded from chromatin. Unloading is driven by polyubiquitylation of MCM7, a subunit of the terminated replicative helicase, and processed by p97/VCP segregase. Most of our knowledge of replication termination comes from model organisms, and little is known about how this process is executed and regulated in human somatic cells. Here we show that replisome disassembly in this system requires CUL2-driven MCM7 ubiquitylation, p97, and UBXN7 for unloading and provide evidence for "backup" mitotic replisome disassembly, demonstrating conservation of such mechanisms. Finally, we find that small-molecule inhibitors against Cullin ubiquitin ligases (CULi) and p97 (p97i) affect replisome unloading but also lead to induction of replication stress in cells, which limits their usefulness to specifically target replisome disassembly processes.

Citing Articles

USP37 prevents unscheduled replisome unloading through MCM complex deubiquitination.

Bolhuis D, Fleifel D, Bonacci T, Wang X, Mouery B, Cook J bioRxiv. 2024; .

PMID: 39282338 PMC: 11398414. DOI: 10.1101/2024.09.03.610997.

A Decade of Discovery-Eukaryotic Replisome Disassembly at Replication Termination.

Jones R, Reynolds-Winczura A, Gambus A Biology (Basel). 2024; 13(4).

PMID: 38666845 PMC: 11048390. DOI: 10.3390/biology13040233.

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