Acute inactivation of the replicative helicase in human cells triggers MCM8-9-dependent DNA synthesis
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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.
In: Genes & Development, Vol. 31, No. 8, 2017, p. 816-829.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Acute inactivation of the replicative helicase in human cells triggers MCM8-9-dependent DNA synthesis
AU - Natsume, Toyoaki
AU - Nishimura, Kohei
AU - Minocherhomji, Sheroy
AU - Bhowmick, Rahul
AU - Hickson, Ian D
AU - Kanemaki, Masato T
N1 - © 2017 Natsume et al.; Published by Cold Spring Harbor Laboratory Press.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
U2 - 10.1101/gad.297663.117
DO - 10.1101/gad.297663.117
M3 - Journal article
C2 - 28487407
VL - 31
SP - 816
EP - 829
JO - Genes & Development
JF - Genes & Development
SN - 0890-9369
IS - 8
ER -
ID: 179437950