Beta Human Papillomavirus 8 E6 Induces Micronucleus Formation and Promotes Chromothripsis

Abstract

Some beta genus human papillomaviruses (β-HPVs) may promote skin carcinogenesis by inducing mutations in the host genome. Supporting this, the E6 protein from β-HPV8 (8 E6) promotes skin cancer in mice with or without UV exposure.

Human papillomavirus E6/E7 oncoproteins promote radiotherapy-mediated tumor suppression by globally hijacking host DNA damage repair

“…In parallel to clonogenic growth analyses, cytokinesis-block micronucleus assays demonstrated that both E6- and E7-transduced cells already displayed an increase of chromosome breakages compared to control cells at basal (non-irradiated) condition. These interesting observations (exacerbated following irradiation) are in agreement with recent studies analyzing the effect of viral oncoproteins from HPV16 as well as of E6 from cutaneous βHPV8 on genome instability 54 , 55 . Finally, the significant slowing of DNA double-strand break repair kinetics observed in case of viral oncoprotein expression further supported the E6/E7-dependent increase of cellular radiosensitivity.…”

Human Papillomavirus-Induced Chromosomal Instability and Aneuploidy in Squamous Cell Cancers

“…However, in HPV-infected cells, p53 is degraded by E6, and Rb is inactivated by E7, both of which result in cell cycle progression to S phase even in the presence of DNA damage, increasing the likelihood of CIN and micronuclei formation [ 64 , 65 , 66 ]. Several serotypes of the β-HPV genus can also induce the formation of micronuclei and subsequently increase tumorigenic mutations in nonmelanoma skin cancer [ 58 ]. HPV8 E6 reduces the availability of Bloom syndrome protein (BLM), which is involved in resolving chromosome bridges during anaphase and facilitating faithful chromosome segregation and results in an increased frequency of micronuclei [ 58 , 67 ].…”

“…Several serotypes of the β-HPV genus can also induce the formation of micronuclei and subsequently increase tumorigenic mutations in nonmelanoma skin cancer [ 58 ]. HPV8 E6 reduces the availability of Bloom syndrome protein (BLM), which is involved in resolving chromosome bridges during anaphase and facilitating faithful chromosome segregation and results in an increased frequency of micronuclei [ 58 , 67 ]. Similarly, HPV38 E6 (also in the β-HPV genus) was shown to be capable of increasing the frequency of micronuclei, although it remains elusive whether the underlying mechanism is identical to that of HPV8 E6 [ 58 ].…”

“…HPV8 E6 reduces the availability of Bloom syndrome protein (BLM), which is involved in resolving chromosome bridges during anaphase and facilitating faithful chromosome segregation and results in an increased frequency of micronuclei [ 58 , 67 ]. Similarly, HPV38 E6 (also in the β-HPV genus) was shown to be capable of increasing the frequency of micronuclei, although it remains elusive whether the underlying mechanism is identical to that of HPV8 E6 [ 58 ]. In summary, numerous studies have shown that micronuclei are a common consequence of CIN elicited by HPV infection.…”

“…Additionally, HPV16 E6 and E7 can affect telomerase activity, leading to telomere shortening and the formation of chromosome bridges in human keratinocytes [57]. Interestingly, the E6 protein of cutaneous beta-genus papillomavirus (β-HPVs) can also cause anaphase bridge formation [58], implying that this functionality may be conserved among E6 proteins [10,44].…”