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.
authors: Department of Microbiology, NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA.
authors: Heidi
authors: H
authors: Karttunen
authors: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Jeffrey N
authors: JN
authors: Savas
authors: Department of Microbiology, NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA.
authors: Caleb
authors: C
authors: McKinney
authors: Department of Biochemistry and Molecular Pharmacology, NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA.
authors: Yu-Hung
authors: YH
authors: Chen
authors: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: John R
authors: JR
authors: Yates
authors: Department of Virology, University of Turku, Turku 20520, Finland.
authors: Veijo
authors: V
authors: Hukkanen
authors: Department of Biochemistry and Molecular Pharmacology, NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA. Electronic address: tony.huang@nyumc.org.
authors: Tony T
authors: TT
authors: Huang
authors: Department of Microbiology, NYU Cancer Institute, NYU School of Medicine, New York, NY 10016, USA. Electronic address: ian.mohr@med.nyu.edu.
authors: Ian
authors: I
authors: Mohr
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004279:DNA, Viral / Q000096:biosynthesis*; D004259:DNA-Directed DNA Polymerase / Q000502:physiology; D005199:Fanconi Anemia / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D051856:Fanconi Anemia Complementation Group Proteins / Q000378:metabolism; D042822:Genomic Instability; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000502:physiology*; D054875:Ubiquitination; D014709:Vero Cells; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D052236:Fanconi Anemia Complementation Group D2 Protein; D051856:Fanconi Anemia Complementation Group Proteins; D004259:DNA-Directed DNA Polymerase