Abstract
Human papillomaviruses (HPVs) have evolved to use the DNA repair machinery to replicate its DNA genome in differentiated cells. HPV activates the DNA damage response (DDR) in infected cells. Cellular DDR factors are recruited to the HPV DNA genome and position the cellular DNA polymerase on the HPV DNA and progeny genomes are synthesized. Following HPV DNA replication, HPV late gene expression is activated. Recent research has shown that the DDR factors also interact with RNA binding proteins and affects RNA processing. DDR factors activated by DNA damage and that associate with HPV DNA can recruit splicing factors and RNA binding proteins to the HPV DNA and induce HPV late gene expression. This induction is the result of altered alternative polyadenylation and splicing of HPV messenger RNA (mRNA). HPV uses the DDR machinery to replicate its DNA genome and to activate HPV late gene expression at the level of RNA processing.
Highlights
Human papillomaviruses (HPVs) are small DNA viruses that infect the keratinocytes of squamous and mucosal epithelia [1,2]
This activation is a consequence of the replication stress that arises from replication of the HPV genome, the unspecific DNA helicase activity of E1, the aberrant cell cycle entry created by the viral proteins or the single stranded DNA (ssDNA) generated during homologous recombination (HR)-mediated productive HPV replication [43]
Recruitment of E2 to the DNA genome is required for HPV DNA replication and HPV E2 contributes to induction of HPV late gene expression by inhibiting the HPV early polyadenylation signal pAE
Summary
Human papillomaviruses (HPVs) are small DNA viruses that infect the keratinocytes of squamous and mucosal epithelia [1,2]. The HPV genome encodes two late (L) genes, which encode the L1 and L2 structural proteins that are expressed only in terminally differentiated keratinocytes in the upper part of the epithelium (Figure 1) [9]. HPV has no means of replicating its own DNA in an ordered expression of the viral genes [10]. ATM and ATR appear to regulate the broadest spectrum of downstream factors (Figure 2) [26,27,28] They induce further phosphorylation events through the activation that contribute to the DDR (Figure 2) [26,27,28]. The DNA downstream events in the DDR signal chain transduction include cell cycle apoptosis. Downstream the signal are cell cycle arrest, repair, apoptosis.ATR is site the of damage.
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