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

E2 displacement of CIP2A from TOPBP1 activates an ATM-high, ATR-low DNA damage response during papillomavirus life cycles, promoting viral replication and cell proliferation.

• Why it matters: Papillomaviruses exploit epithelial differentiation to drive replication, but how E2 triggers DDR to support homologous recombination is unclear.
• What they did: In differentiation, E2 attenuates SIRT1, increases acetylation of DDR factors, and displaces CIP2A from TOPBP1, inhibiting PP2A and activating ATM while reducing TOPBP1-ATR complexes and ATR activation.
• The result: The ATM-high, ATR-low DDR phenotype is observed in E2-expressing keratinocytes, HPV16-positive cells, MmuPV1-induced lesions, HPV-positive head and neck cancer lines, and HPV16-positive patient-derived xenografts; ATM inhibition preferentially kills E2-expressing cells.