The immediate-early protein 1 of human herpesvirus 6B interacts with NBS1 and inhibits ATM signaling

Viral infection often trigger an ATM serine/threonine kinase (ATM)-dependent DNA damage response in host cells that suppresses viral replication. Viruses evolved different strategies to counteract this antiviral surveillance system. Here, we report that human herpesvirus 6B (HHV-6B) infection causes genomic instability by suppressing ATM signaling in host cells. Expression of immediate-early protein 1 (IE1) phenocopies this phenotype and blocks homology-directed double-strand break repair. Mechanistically, IE1 interacts with NBS1, and inhibits ATM signaling through two distinct domains. HHV-6B seems to efficiently inhibit ATM signaling as further depletion of either NBS1 or ATM do not significantly boost viral replication in infected cells. Interestingly, viral integration of HHV-6B into the host's telomeres is not strictly dependent on NBS1, challenging current models where integration occurs through homology-directed repair. Given that spontaneous IE1 expression has been detected in cells of subjects with inherited chromosomally-integrated form of HHV-6B (iciHHV-6B), a condition associated with several health conditions, our results raise the possibility of a link between genomic instability and the development of iciHHV-6-associated diseases. HHV-6B, the etiologic agent of Roseola Infantum in children, induces genomic instability in infected cells. This study reveals new domains in the HHV-6B IE1 protein, crucial for damage site accumulation and ATM-dependent signaling inhibition.HHV-6B infection inhibits DNA damage signaling. The HHV-6B IE1 protein specifically blocks HDR-mediated repair. HHV-6B IE1 is recruited to sites of DNA damage through its interaction with the BRCT2 domain of NBS1. The C-terminal domain of HHV-6B IE1 protein is responsible for the inhibition of ATM signaling. HHV-6B, the etiologic agent of Roseola Infantum in children, induces genomic instability in infected cells. This study reveals new domains in the HHV-6B IE1 protein, crucial for damage site accumulation and ATM-dependent signaling inhibition.