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Review
. 2018 Sep 6;73(suppl 1):e539s.
doi: 10.6061/clinics/2018/e539s.

Human papillomavirus and genome instability: from productive infection to cancer

Bruna Prati  1 , Bruna Marangoni  1 , Enrique Boccardo  1
Affiliations
Review

Human papillomavirus and genome instability: from productive infection to cancer

Bruna Prati et al. Clinics (Sao Paulo). .

Abstract

Infection with high oncogenic risk human papillomavirus types is the etiological factor of cervical cancer and a major cause of other epithelial malignancies, including vulvar, vaginal, anal, penile and head and neck carcinomas. These agents affect epithelial homeostasis through the expression of specific proteins that deregulate important cellular signaling pathways to achieve efficient viral replication. Among the major targets of viral proteins are components of the DNA damage detection and repair machinery. The activation of many of these cellular factors is critical to process viral genome replication intermediates and, consequently, to sustain faithful viral progeny production. In addition to the important role of cellular DNA repair machinery in the infective human papillomavirus cycle, alterations in the expression and activity of many of its components are observed in human papillomavirus-related tumors. Several studies from different laboratories have reported the impact of the expression of human papillomavirus oncogenes, mainly E6 and E7, on proteins in almost all the main cellular DNA repair mechanisms. This has direct consequences on cellular transformation since it causes the accumulation of point mutations, insertions and deletions of short nucleotide stretches, as well as numerical and structural chromosomal alterations characteristic of tumor cells. On the other hand, it is clear that human papillomavirus-transformed cells depend on the preservation of a basal cellular DNA repair activity level to maintain tumor cell viability. In this review, we summarize the data concerning the effect of human papillomavirus infection on DNA repair mechanisms. In addition, we discuss the potential of exploiting human papillomavirus-transformed cell dependency on DNA repair pathways as effective antitumoral therapies.

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Conflict of interest statement

No potential conflict of interest was reported.

Figures

Figure 1
Figure 1
Interplay between HPV and cellular DNA repair machinery during infective viral cycle and virus-mediated cell transformation. A) During productive infection, HPV origin of replication (Ori) is triggered several times during the same cell cycle, leading to the “onion skin” type of DNA replication. To mediate genome amplification and process the viral genome replication intermediates, HPV activates and recruits several components of the DNA damage response (DDR), including 53BP1, ATRIP, OPbp1, p-ATM, p-H2AX, p-p53, ATR, CHK1, CHK2, PCNA, RPA, NBS1, BRCA1, RAD51, MRE11 and Ku70/80. HPV integration into the cellular genome may arise as a consequence of active DNA break repair. This event leads to E2 downregulation and increases the levels of E6 and E7 transcripts and proteins. B) In parallel to viral genome amplification, HPV oncogene expression increases the cell life span, induces alterations in chromosome segregation, prevents apoptosis and affects DNA repair, leading to the accumulation of alterations in cellular DNA. C) The presence of E2 protein either expressed from coexisting episomal viral genomes or derived from reinfection with the same or a different HPV type may trigger the replication of integrated HPV genomes, causing the rapid appearance of chromosome breaks and rearrangements, further contributing to malignant transformation. For references, see the main text.
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