Plays several roles to favor viral DNA replication including disruption of host intranuclear speckles (termed ND10 body) organization, cell cycle arrest at the G2 phase and inhibition of cellular DNA replication, by preventing loading of host replication licensing proteins MCM2 and MCM7 onto chromatin (By similarity). Additionally, E4 is found in inclusion bodies within the cytoplasm associated with host SRPK1, a splicing factor regulator. Therefore, E4 may regulate host splicing factors in order to favor expression of late viral transcripts. Late in the infectious cycle, E4 may also act to diminish the integrity of the keratinocyte by disrupting the keratin cytoskeleton and inducing apoptosis through alteration of mitochondrial function to facilitate egress of the newly formed virions.