HELLS and infection: We identified that (i) RECQL4, SMARCA6, SQSTM1, and DCAF1 are degradation targets of Ad5 early proteins; (ii) SMARCAD1 and SMC6 are associated with replicating DNA genomes in the absence of Ad5 E4 early proteins; and (iii) SMARCAD1 and SMC family components SMC5 and SMC6 exert subtle inhibitory effects on infection.