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Dysregulation or failure of these pathways results in cancers and genetic disease. DNA viruses, including the herpesvirus cytomegalovirus (CMV), activate DDR signaling during their replicative program. The mechanisms by which they commandeer these responses for replication of their genome remain unclear. Here, we define a viral protein, UL138, that modulates the activity of host DDR pathways. The loss of UL138 results in structural variants, including inversions, deletions, and duplications, with signature of homology-directed repair and other DDR pathways. The actions of UL138 are due, in part, to its modulation of pathways regulated by the cellular deubiquitinating complex that targets proliferating cell nuclear antigen (PCNA) and Fanconi Anemia effectors, FANCD2 and FANCI. However, we also show that UL138 accesses pathways independent of USP1\u2013PCNA\/FANCD2\/FANCI. Disruption of UL138 or these pathways impacted viral genome replication and had consequences for viral genome integrity. This work provides mechanistic insight into the long-standing questions of how DNA viruses recruit, modulate and use cellular DDR pathways. It also puts forth CMV as a model system for further defining these pathways in human cells.<\/jats:p>","DOI":"10.1093\/nar\/gkaf1445","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T13:31:10Z","timestamp":1764941470000},"source":"Crossref","is-referenced-by-count":2,"title":["Human cytomegalovirus regulates host DNA repair machinery for viral genome integrity"],"prefix":"10.1093","volume":"54","author":[{"given":"Pierce","family":"Longmire","sequence":"first","affiliation":[{"name":"Graduate Program in Molecular Medicine, University of Arizona , Tucson, AZ 85719 ,","place":["United States"]},{"name":"Department of Immunobiology, University of Arizona , Tucson, AZ 85719 ,","place":["United States"]},{"name":"BIO5 Institute, University of Arizona , Tucson, AZ 85719 ,","place":["United States"]},{"name":"Current affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104 ,","place":["United States"]},{"name":"Current affiliation: Division of Protective Immunity, Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Zeltzer","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, University of Arizona , Tucson, AZ 85719 ,","place":["United States"]},{"name":"BIO5 Institute, University of Arizona , Tucson, AZ 85719 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen","family":"Zarrella","sequence":"additional","affiliation":[{"name":"Graduate Program in Molecular Medicine, University of Arizona , Tucson, AZ 85719 ,","place":["United States"]},{"name":"Department of Immunobiology, University of Arizona , Tucson, AZ 85719 ,","place":["United States"]},{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine , Aurora, CO 80045 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Daigle","sequence":"additional","affiliation":[{"name":"Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth , Hanover, NH 03755 ,","place":["United States"]},{"name":"Research Computing and Data Services, Information, Technology, and Consulting, Dartmouth College , Hanover, NH 03755 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marek","family":"Svoboda","sequence":"additional","affiliation":[{"name":"Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth , Hanover, NH 03755 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin M","family":"Reitsma","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI 53226 ,","place":["United States"]},{"name":"AbbVie Inc. , North Chicago, IL 60085 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott S","family":"Terhune","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Medical College of Wisconsin , Milwaukee, WI 53226 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8631-4753","authenticated-orcid":false,"given":"Carly","family":"Bobak","sequence":"additional","affiliation":[{"name":"Research Computing and Data Services, Information, Technology, and Consulting, Dartmouth College , Hanover, NH 03755 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Bosco","sequence":"additional","affiliation":[{"name":"Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth , Hanover, NH 03755 ,","place":["United 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