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Distinct mechanistic responses to replication fork stalling induced by either nucleotide or protein deprivation.


ABSTRACT: Incidents that slow or stall replication fork progression, collectively known as replication stress, represent a major source of spontaneous genomic instability. Here, we determine the requirement for global protein biosynthesis on DNA replication and associated downstream signaling. We study this response side by side with dNTP deprivation; one of the most commonly used means to investigate replication arrest and replicative stress. Our in vitro interrogations reveal that inhibition of translation by cycloheximide (CHX) rapidly impairs replication fork progression without decoupling helicase and polymerase activities or inducing DNA damage. In line with this, protein deprivation stress does not activate checkpoint signaling. In contrast to the direct link between insufficient dNTP pools and genome instability, our findings suggest that replication forks remain stable during short-term protein deficiency. We find that replication forks initially endure fluctuations in protein supply in order to efficiently resume DNA synthesis upon reversal of the induced protein deprivation stress. These results reveal distinct cellular responses to replication arrest induced by deprivation of either nucleotides or proteins.

SUBMITTER: Henriksson S 

PROVIDER: S-EPMC5969565 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Distinct mechanistic responses to replication fork stalling induced by either nucleotide or protein deprivation.

Henriksson Sofia S   Groth Petra P   Gustafsson Nina N   Helleday Thomas T  

Cell cycle (Georgetown, Tex.) 20180402 5


Incidents that slow or stall replication fork progression, collectively known as replication stress, represent a major source of spontaneous genomic instability. Here, we determine the requirement for global protein biosynthesis on DNA replication and associated downstream signaling. We study this response side by side with dNTP deprivation; one of the most commonly used means to investigate replication arrest and replicative stress. Our in vitro interrogations reveal that inhibition of translat  ...[more]

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