Acute Inactivation of the Replicative Helicase in Human Cells Triggers MCM8-9-dependent DNA Synthesis

Overview

Journal Genes Dev

Specialty Molecular Biology

Date 2017 May 11

PMID 28487407

Citations 32

Authors

Toyoaki Natsume

Kohei Nishimura

Sheroy Minocherhomji

Rahul Bhowmick

Ian D Hickson

Masato T Kanemaki

Affiliations

Soon will be listed here.

Abstract

DNA replication fork progression can be disrupted at difficult to replicate loci in the human genome, which has the potential to challenge chromosome integrity. This replication fork disruption can lead to the dissociation of the replisome and the formation of DNA damage. To model the events stemming from replisome dissociation during DNA replication perturbation, we used a degron-based system for inducible proteolysis of a subunit of the replicative helicase. We show that MCM2-depleted cells activate a DNA damage response pathway and generate replication-associated DNA double-strand breaks (DSBs). Remarkably, these cells maintain some DNA synthesis in the absence of MCM2, and this requires the MCM8-9 complex, a paralog of the MCM2-7 replicative helicase. We show that MCM8-9 functions in a homologous recombination-based pathway downstream from RAD51, which is promoted by DSB induction. This RAD51/MCM8-9 axis is distinct from the recently described RAD52-dependent DNA synthesis pathway that operates in early mitosis at common fragile sites. We propose that stalled replication forks can be restarted in S phase via homologous recombination using MCM8-9 as an alternative replicative helicase.

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