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Review
. 2020 Jul 10;12(7):744.
doi: 10.3390/v12070744.

Regulation of the Human Papillomavirus Life Cycle by DNA Damage Repair Pathways and Epigenetic Factors

Ekaterina Albert  1 , Laimonis Laimins  1
Affiliations
Review

Regulation of the Human Papillomavirus Life Cycle by DNA Damage Repair Pathways and Epigenetic Factors

Ekaterina Albert et al. Viruses. .

Abstract

Human papillomaviruses are the causative agents of cervical and other anogenital cancers along with approximately 60% of oropharyngeal cancers. These small double-stranded DNA viruses infect stratified epithelia and link their productive life cycles to differentiation. HPV proteins target cellular factors, such as those involved in DNA damage repair, as well as epigenetic control of host and viral transcription to regulate the productive life cycle. HPVs constitutively activate the ATM and ATR DNA repair pathways and preferentially recruit these proteins to viral genomes to facilitate productive viral replication. In addition, the sirtuin deacetylases along with histone acetyltransferases, including Tip60, are targeted in HPV infections to regulate viral transcription and replication. These pathways provide potential targets for drug therapy to treat HPV-induced disease.

Keywords: ATM; ATR; DNA damage; HPV; Tip60; sirtuins.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
HPV 31 genome map showing the upstream regulatory region (URR), early genes E1, E2, E4, and E5, as well as late capsid genes L1 and L2. The early promoter is designated p97, while the late differentiation-dependent promoter is p742. Early and late poly A sites are shown.
Figure 2
Figure 2
HPV life cycle. Normal keratinocytes are shown on the left, while HPV-infected keratinocytes are shown on the right. HPV virions infect basal cells that become exposed upon wounding. Following entry, low-copy episomes are established in undifferentiated cells and are transmitted to daughter cells, one of which goes on to differentiate. Upon differentiation, genome amplification is induced, along with late promoter activation. This is followed by virion assembly and release.
Figure 3
Figure 3
ATM and ATR DNA damage repair pathways. Upon DNA damage, the MRE11-RAD50-NBS1 (MRN) complex recruits ATM to the site where it undergoes autophosphorylation. The activated ATM kinase then phosphorylates the histone H2AX, CHK2, SMC1, and other downstream effectors. At the same time, ATR is activated by phosphorylation through association with TOPBP1 and ATRIP, leading to phosphorylation of CHK1, H2AX, TOPBP1, and ATRIP. This leads to phosphorylation of hundreds of downstream factors, resulting in homologous recombination repair in G2/M.
See this image and copyright information in PMC

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