The curious case of APOBEC3 activation by cancer-associated human papillomaviruses

Wallace, Nicholas A.; Münger, Karl

doi:10.1371/journal.ppat.1006717

Cited by 25 publications

(27 citation statements)

References 26 publications

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“…While we confirmed the exclusivity of HPV infection and TP53, CDKN2A and TERT mutations in head and neck tumors, we could also link virus presence to an increase in mutations attributed to the mutational signature 2 54 . These are explained by the activity of APOBEC, whichamong other effectschanges viral genome sequences as a mechanism of cellular defense against viruses 55,56 . This activation could play an important role in introducing further host genome alterations and, thus, constitute an important mechanism driving tumorigenesis 32,56 .…”

Section: Discussionmentioning

confidence: 99%

The landscape of viral associations in human cancers

Zapatka

Borozan

Brewer

et al. 2018

Preprint

103

150

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Potential viral pathogens were systematically investigated in the whole-genome and transcriptome sequencing of 2,656 donors as part of the Pan-Cancer Analysis of Whole Genomes using a consensus approach integrating three independent pathogen detection pipelines. Viruses were detected in 382 genomic and 68 transcriptome data sets. We extensively searched and characterized numerous features of virus-positive cancers integrating various PCAWG datasets. We show the high prevalence of known tumor associated viruses such as EBV, HBV and several HPV types. Our systematic analysis revealed that HPV presence was significantly exclusive with well-known driver mutations in head/neck cancer. A strong association was observed between HPV infection and the APOBEC mutational signatures, suggesting the role of impaired mechanism of antiviral cellular defense as a driving force in the development of cervical, bladder and head neck carcinoma. Viral integration into the host genome was observed for HBV, HPV16, HPV18 and AAV2 and associated with a local increase in copy number variations. The recurrent viral integrations at the TERT promoter were coupled to high telomerase expression uncovering a further mechanism to activate this tumor driving process. High levels of endogenous retrovirus ERV1 expression is linked to worse survival outcome in kidney cancer.

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Section: Discussionmentioning

confidence: 99%

The landscape of viral associations in human cancers

Zapatka

Borozan

Brewer

et al. 2018

Preprint

103

150

View full text Add to dashboard Cite

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“…Therefore, HPV sequence integration during malignant transformation is accompanied by enhanced APOBEC3A levels [ 67 ]. Consistently, not only cervical squamous cell carcinomas but also other HPV-associated malignancies exhibit APOBEC3 mutational signatures [ 47 , 54 , 55 , 68 ]. A study comparing the HPV+ and HPV- head and neck squamous cell carcinoma found significantly increased expression of APOBEC3B and increased level of TCW mutations in HPV positive tumors than HPV negative tumors suggesting a strong link between HPV and APOBEC-mediated mutagenesis of cellular genes [ 59 ].…”

Section: Apobec3 and Cervical Cancermentioning

confidence: 94%

APOBEC: A molecular driver in cervical cancer pathogenesis

et al. 2021

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Cervical cancer is one of the foremost common cancers in women. Human papillomavirus (HPV) infection remains a major risk factor of cervical cancer. In addition, numerous other genetic and epigenetic factors also are involved in the underlying pathogenesis of cervical cancer. Recently, it has been reported that apolipoprotein B mRNA editing enzyme catalytic polypeptide like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. Particularly, the APOBEC3 family was shown to induce tumor mutations by aberrant DNA editing mechanism. In general, APOBEC3 enzymes play a pivotal role in the deamination of cytidine to uridine in DNA and RNA to control diverse biological processes such as regulation of protein expression, innate immunity, and embryonic development. Innate antiviral activity of the APOBEC3 family members restrict retroviruses, endogenous retro-element, and DNA viruses including the HPV that is the leading risk factor for cervical cancer. This review briefly describes the pathogenesis of cervical cancer and discusses in detail the recent findings on the role of APOBEC in the molecular pathogenesis of cervical cancer.

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“…Indeed, deamination of the remaining TC motifs are most of the time non-synonymous. On the other hand, the deaminase activity could positively impact viral fitness by participating to the genetic diversification of the virus or even by protecting the host cell against the reactivation of retroelements [50,51]. We speculate that the error rate of the host DNA polymerase could be too low for viruses with such small DNA genome, hence requiring the A3 editing activity to drive their evolution.…”

Section: Plos Pathogensmentioning

confidence: 97%

Footprint of the host restriction factors APOBEC3 on the genome of human viruses

et al. 2020

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APOBEC3 enzymes are innate immune effectors that introduce mutations into viral genomes. These enzymes are cytidine deaminases which transform cytosine into uracil. They preferentially mutate cytidine preceded by thymidine making the 5'TC motif their favored target. Viruses have evolved different strategies to evade APOBEC3 restriction. Certain viruses actively encode viral proteins antagonizing the APOBEC3s, others passively face the APOBEC3 selection pressure thanks to a depleted genome for APOBEC3-targeted motifs. Hence, the APOBEC3s left on the genome of certain viruses an evolutionary footprint. The aim of our study is the identification of these viruses having a genome shaped by the APOBEC3s. We analyzed the genome of 33,400 human viruses for the depletion of APO-BEC3-favored motifs. We demonstrate that the APOBEC3 selection pressure impacts at least 22% of all currently annotated human viral species. The papillomaviridae and polyomaviridae are the most intensively footprinted families; evidencing a selection pressure acting genome-wide and on both strands. Members of the parvoviridae family are differentially targeted in term of both magnitude and localization of the footprint. Interestingly, a massive APOBEC3 footprint is present on both strands of the B19 erythroparvovirus; making this viral genome one of the most cleaned sequences for APOBEC3-favored motifs. We also identified the endemic coronaviridae as significantly footprinted. Interestingly, no such footprint has been detected on the zoonotic MERS-CoV, SARS-CoV-1 and SARS-CoV-2 coronaviruses. In addition to viruses that are footprinted genome-wide, certain viruses are footprinted only on very short sections of their genome. That is the case for the gamma-herpesviridae and adenoviridae where the footprint is localized on the lytic origins of replication. A mild footprint can also be detected on the negative strand of the reverse transcribing HIV-1, HIV-2, HTLV-1 and HBV viruses. Together, our data illustrate the extent of the APOBEC3 selection pressure on the human viruses and identify new putatively APOBEC3-targeted viruses.

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The curious case of APOBEC3 activation by cancer-associated human papillomaviruses

Cited by 25 publications

References 26 publications

The landscape of viral associations in human cancers

The landscape of viral associations in human cancers

APOBEC: A molecular driver in cervical cancer pathogenesis

Footprint of the host restriction factors APOBEC3 on the genome of human viruses

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