The results expand our understanding of DDR proteins that regulate the HPV16 life cycle and suggest that inhibition of SMARCAL1 function represents a novel antiviral strategy for the treatment and prevention of HPV infections.IMPORTANCEHuman papillomavirus 16 (HPV16) is responsible for the majority of HPV+ cancers, contributing to 54% of cervical cancers and ~90% of HPV+HNSCC. This evidence concerns the gene SMARCAL1 and cancer.