Human cytomegalovirus regulates host DNA repair machinery for viral genome integrity. Nucleic Acids Res 2026 Jan 14;54(2)
Date
01/15/2026Pubmed ID
41533576Pubmed Central ID
PMC12802892DOI
10.1093/nar/gkaf1445Scopus ID
2-s2.0-105027600485 (requires institutional sign-in at Scopus site) 1 CitationAbstract
The DNA damage response (DDR) encompasses a multitude of interconnected pathways that serve as a cellular defense to protect genome integrity. 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-PCNA/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.
Author List
Longmire P, Zeltzer S, Zarrella K, Daigle O, Svoboda M, Reitsma JM, Terhune SS, Bobak C, Bosco G, Goodrum FAuthor
Scott Terhune PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
CytomegalovirusDNA Damage
DNA Repair
DNA Replication
Genome, Viral
Host-Pathogen Interactions
Humans
Proliferating Cell Nuclear Antigen
Viral Proteins
Virus Replication
