Co-opting the Fanconi anemia genomic stability pathway enables herpesvirus DNA synthesis and productive growth

Heidi S. Karttunen, Jeffrey N. Savas, Caleb McKinney, Yu Hung Chen, John R. Yates, Veijo Hukkanen, Tony T. Huang, Ian Mohr

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

DNA damage associated with viral DNA synthesis can result in double-strand breaks that threaten genome integrity and must be repaired. Here, we establish that the cellular Fanconi anemia (FA) genomic stability pathway is exploited by herpes simplex virus 1 (HSV-1) to promote viral DNA synthesis and enable its productive growth. Potent FA pathway activation in HSV-1-infected cells resulted in monoubiquitination of FA effector proteins FANCI and FANCD2 (FANCI-D2) and required the viral DNA polymerase. FANCD2 relocalized to viral replication compartments, and FANCI-D2 interacted with a multisubunit complex containing the virus-encoded single-stranded DNA-binding protein ICP8. Significantly, whereas HSV-1 productive growth was impaired in monoubiquitination-defective FA cells, this restriction was partially surmounted by antagonizing the DNA-dependent protein kinase (DNA-PK), a critical enzyme required for nonhomologous end-joining (NHEJ). This identifies the FA-pathway as a cellular factor required for herpesvirus productive growth and suggests that FA-mediated suppression of NHEJ is a fundamental step in the viral life cycle.

Original languageEnglish (US)
Pages (from-to)111-122
Number of pages12
JournalMolecular Cell
Volume55
Issue number1
DOIs
StatePublished - Jul 3 2014
Externally publishedYes

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Fanconi Anemia
Genomic Instability
Herpesviridae
Viral DNA
Human Herpesvirus 1
DNA
Growth
Fanconi Anemia Complementation Group Proteins
DNA-Activated Protein Kinase
DNA-Binding Proteins
DNA-Directed DNA Polymerase
Life Cycle Stages
DNA Damage
Genome
Viruses
Enzymes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Co-opting the Fanconi anemia genomic stability pathway enables herpesvirus DNA synthesis and productive growth. / Karttunen, Heidi S.; Savas, Jeffrey N.; McKinney, Caleb; Chen, Yu Hung; Yates, John R.; Hukkanen, Veijo; Huang, Tony T.; Mohr, Ian.

In: Molecular Cell, Vol. 55, No. 1, 03.07.2014, p. 111-122.

Research output: Contribution to journalArticle

Karttunen, HS, Savas, JN, McKinney, C, Chen, YH, Yates, JR, Hukkanen, V, Huang, TT & Mohr, I 2014, 'Co-opting the Fanconi anemia genomic stability pathway enables herpesvirus DNA synthesis and productive growth', Molecular Cell, vol. 55, no. 1, pp. 111-122. https://doi.org/10.1016/j.molcel.2014.05.020
Karttunen, Heidi S. ; Savas, Jeffrey N. ; McKinney, Caleb ; Chen, Yu Hung ; Yates, John R. ; Hukkanen, Veijo ; Huang, Tony T. ; Mohr, Ian. / Co-opting the Fanconi anemia genomic stability pathway enables herpesvirus DNA synthesis and productive growth. In: Molecular Cell. 2014 ; Vol. 55, No. 1. pp. 111-122.
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