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

• Published in: PLoS pathogens 2018-01, Vol.14 (1), p.e1006717
• Main Authors: Wallace, Nicholas A, Münger, Karl
• Format: Article
• Language: English
• Subjects: Adaptive immunity; APOBEC Deaminases; Apolipoproteins; Apoptosis; Biology and Life Sciences; Cancer; Cell cycle; Cytidine Deaminase; Cytosine Deaminase - chemistry; Cytosine Deaminase - genetics; Cytosine Deaminase - metabolism; Deoxyribonucleic acid; DNA; Enzyme Activation; Enzyme Induction; Enzymes; Epithelium - metabolism; Epithelium - pathology; Epithelium - virology; Gene expression; Genetic aspects; Genomes; Hepatitis; Human papillomavirus; Humans; Infections; Kinases; Medicine and Health Sciences; Models, Biological; Mutagenesis; Mutation; Neoantigens; Neoplasm Proteins - agonists; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - virology; Opinion; Papillomaviridae - pathogenicity; Papillomaviridae - physiology; Papillomavirus; Papillomavirus Infections - genetics; Papillomavirus Infections - metabolism; Papillomavirus Infections - virology; Polypeptides; Proteins; Risk factors; Senescence; Viral Proteins - genetics; Viral Proteins - metabolism; Virus Integration; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006717

The degradation of RB1 by HR-HPV E7 proteins is therefore predicted to cause transcription of repetitive elements [18]. [...]HR-HPV-infected cells would gain significant advantages from this A3-dependent restriction of LINE elements. Because even unrestrained A3 activity will not completely prevent retrotransposition, the residual activation of double-strand DNA break sensing and repair machinery may be beneficial for efficient HR-HPV genome replication given its well-documented dependence on these factors, including the Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia And Rad3-Related Protein (ATR) kinases [22]. [...]HR-HPVs may benefit from a deaminase-independent activity of A3, making the A3 mutational signature in HPV-associated tumors simply a by-product of the viruses’ requirement for another function of A3. Because nearly every unvaccinated, sexually active individual has been infected with an HR-HPV, such an incredibly successful virus should have evolved a defensive strategy against the potent restriction of viral replication and viral persistence by A3 unless it provides them with a selective advantage. While activation of double-strand DNA sensing and repair pathways induced by retrotransposition triggered by RB1 degradation and R-loop resolution by A3s may stimulate HR-HPV genome replication and progeny synthesis, A3 restriction of repetitive elements may protect HR-HPV-infected cells from undergoing excessive, lethal DNA damage and genomic instability. [...]A3 restriction will prevent elimination of HR-HPV-infected cells by adaptive immune responses to neoantigen expression due to expression of repetitive elements.