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Cell Rep. 2017 May 2;19(5):1022-1032. doi: 10.1016/j.celrep.2017.04.025.

Cytoplasmic ATR Activation Promotes Vaccinia Virus Genome Replication.

Author information

1
Cellular Signalling and Cytoskeletal Function Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
2
High Throughput Screening Facility, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
3
Cellular Signalling and Cytoskeletal Function Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK. Electronic address: michael.way@crick.ac.uk.

Abstract

In contrast to most DNA viruses, poxviruses replicate their genomes in the cytoplasm without host involvement. We find that vaccinia virus induces cytoplasmic activation of ATR early during infection, before genome uncoating, which is unexpected because ATR plays a fundamental nuclear role in maintaining host genome integrity. ATR, RPA, INTS7, and Chk1 are recruited to cytoplasmic DNA viral factories, suggesting canonical ATR pathway activation. Consistent with this, pharmacological and RNAi-mediated inhibition of canonical ATR signaling suppresses genome replication. RPA and the sliding clamp PCNA interact with the viral polymerase E9 and are required for DNA replication. Moreover, the ATR activator TOPBP1 promotes genome replication and associates with the viral replisome component H5. Our study suggests that, in contrast to long-held beliefs, vaccinia recruits conserved components of the eukaryote DNA replication and repair machinery to amplify its genome in the host cytoplasm.

KEYWORDS:

ATR; Chk1; DNA replication; PCNA; RPA; vaccinia virus; viral replisome

PMID:
28467896
PMCID:
PMC5437729
DOI:
10.1016/j.celrep.2017.04.025
[Indexed for MEDLINE]
Free PMC Article

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