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

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

doi:10.1016/j.molcel.2014.05.020

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

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

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

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 language	English (US)
Pages (from-to)	111-122
Number of pages	12
Journal	Molecular cell
Volume	55
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2014.05.020
State	Published - Jul 3 2014

Funding

We thank members of the Mohr lab and A. Wilson for many discussions and Y. Deng at the NYU SOM Microscopy core for assistance. We are most grateful to D. Coen, A. D’Andrea, T. Taniguchi, M. Grompe, S. Weller, and N. DeLuca for generously providing virus strains, FA patient-derived cells, antisera, and shRNA vectors. This work was supported by NIH Grants AI073898 and GM056927 (to I.M.), GM084244 (to T.T.H.), P41 GM103533 (to J.R.Y.), and American Cancer Society grant RSG-12-158-01-DMC (to T.T.H). H.K. and V.H. were supported in part by Academy of Finland grants (123356, 218425 to H.K.; 259725 to V.H.), J.N.S. is supported by NIH grants F32 AG039127 and K99DC013805, and C.M. was supported in part by NIH training grant T32 AI007180.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2014.05.020

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

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.",

author = "Heidi Karttunen and Savas, {Jeffrey N.} and Caleb McKinney and Chen, {Yu Hung} and Yates, {John R.} and Veijo Hukkanen and Huang, {Tony T.} and Ian Mohr",

note = "Funding Information: We thank members of the Mohr lab and A. Wilson for many discussions and Y. Deng at the NYU SOM Microscopy core for assistance. We are most grateful to D. Coen, A. D{\textquoteright}Andrea, T. Taniguchi, M. Grompe, S. Weller, and N. DeLuca for generously providing virus strains, FA patient-derived cells, antisera, and shRNA vectors. This work was supported by NIH Grants AI073898 and GM056927 (to I.M.), GM084244 (to T.T.H.), P41 GM103533 (to J.R.Y.), and American Cancer Society grant RSG-12-158-01-DMC (to T.T.H). H.K. and V.H. were supported in part by Academy of Finland grants (123356, 218425 to H.K.; 259725 to V.H.), J.N.S. is supported by NIH grants F32 AG039127 and K99DC013805, and C.M. was supported in part by NIH training grant T32 AI007180. ",

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doi = "10.1016/j.molcel.2014.05.020",

language = "English (US)",

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AU - Yates, John R.

AU - Hukkanen, Veijo

AU - Huang, Tony T.

AU - Mohr, Ian

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N2 - 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.

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

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