E2 displacement of CIP2A from TOPBP1 activates the DNA damage response during papillomavirus life cycles

The papillomavirus life cycle is linked to epithelial differentiation, and the virus manipulates differentiation to facilitate viral production. One such manipulation is the activation of the DNA damage response (DDR), which promotes viral replication via homologous recombination. Here, we show that the papillomavirus transcription/replication/segregation factor E2 activates the DDR. During differentiation, E2 attenuates sirtuin 1 (SIRT1) activity, enhances the acetylation of DDR factors, and displaces cancerous inhibitor of protein phosphatase 2A (CIP2A) from DNA topoisomerase II-binding protein 1 (TOPBP1), resulting in CIP2A-mediated inhibition of protein phosphatase 2A (PP2A) and ataxia-telangiectasia mutated (ATM) activation. E2 associates with TOPBP1 and ATM while reducing TOPBP1-ATR complexes and ataxia-telangiectasia and Rad3-related (ATR) activation. This ATM-high, ATR-low DDR phenotype promotes viral replication and cell proliferation. We observe this DDR activation in E2-expressing keratinocytes, human papillomavirus 16 (HPV16)-positive cells, Mus musculus papillomavirus 1 (MmuPV1)-induced lesions, HPV-positive head and neck cancer cell lines, and HPV16-positive patient-derived xenografts. ATM inhibition preferentially kills E2-expressing cells, supporting ATM signaling as a potential therapeutic target in HPV-associated disease retaining E2 expression and episomal genomes.