# Human cytomegalovirus regulates host DNA repair machinery for viral genome integrity

## TL;DR

This study reveals how human cytomegalovirus manipulates the host's DNA repair system to maintain its own genome integrity during replication.

## Contribution

The study identifies a viral protein, UL138, that modulates host DNA damage response pathways to regulate viral genome replication.

## Key findings

- Loss of UL138 leads to structural genome variants with homology-directed repair signatures.
- UL138 modulates DDR pathways involving PCNA and Fanconi Anemia effectors.
- Disruption of UL138 or related pathways affects viral genome replication and integrity.

## Abstract

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.

Graphical Abstract