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Acute inactivation of the replicative helicase in human cells triggers MCM8–9-dependent DNA synthesis

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 stemmin...

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Autores principales: Natsume, Toyoaki, Nishimura, Kohei, Minocherhomji, Sheroy, Bhowmick, Rahul, Hickson, Ian D., Kanemaki, Masato T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435893/
https://www.ncbi.nlm.nih.gov/pubmed/28487407
http://dx.doi.org/10.1101/gad.297663.117
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author Natsume, Toyoaki
Nishimura, Kohei
Minocherhomji, Sheroy
Bhowmick, Rahul
Hickson, Ian D.
Kanemaki, Masato T.
author_facet Natsume, Toyoaki
Nishimura, Kohei
Minocherhomji, Sheroy
Bhowmick, Rahul
Hickson, Ian D.
Kanemaki, Masato T.
author_sort Natsume, Toyoaki
collection PubMed
description 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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spelling pubmed-54358932017-10-15 Acute inactivation of the replicative helicase in human cells triggers MCM8–9-dependent DNA synthesis Natsume, Toyoaki Nishimura, Kohei Minocherhomji, Sheroy Bhowmick, Rahul Hickson, Ian D. Kanemaki, Masato T. Genes Dev Research Paper 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. Cold Spring Harbor Laboratory Press 2017-04-15 /pmc/articles/PMC5435893/ /pubmed/28487407 http://dx.doi.org/10.1101/gad.297663.117 Text en © 2017 Natsume et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research Paper
Natsume, Toyoaki
Nishimura, Kohei
Minocherhomji, Sheroy
Bhowmick, Rahul
Hickson, Ian D.
Kanemaki, Masato T.
Acute inactivation of the replicative helicase in human cells triggers MCM8–9-dependent DNA synthesis
title Acute inactivation of the replicative helicase in human cells triggers MCM8–9-dependent DNA synthesis
title_full Acute inactivation of the replicative helicase in human cells triggers MCM8–9-dependent DNA synthesis
title_fullStr Acute inactivation of the replicative helicase in human cells triggers MCM8–9-dependent DNA synthesis
title_full_unstemmed Acute inactivation of the replicative helicase in human cells triggers MCM8–9-dependent DNA synthesis
title_short Acute inactivation of the replicative helicase in human cells triggers MCM8–9-dependent DNA synthesis
title_sort acute inactivation of the replicative helicase in human cells triggers mcm8–9-dependent dna synthesis
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435893/
https://www.ncbi.nlm.nih.gov/pubmed/28487407
http://dx.doi.org/10.1101/gad.297663.117
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