Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response
| Autor: | Tia M Morgan, Joe S. Mymryk, Amélie Fradet-Turcotte, Elise Biquand, Elise G. Lavoie, Sophie Blanchet, Justine Sitz, Maxime Galloy, Julien Dessapt, Steven F. Gameiro, Cary A. Moody, Brandon C Smith, Andréanne Blondeau |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Genome instability
DNA Repair DNA repair DNA damage Papillomavirus E7 Proteins Ubiquitin-Protein Ligases viruses Uterine Cervical Neoplasms Biology medicine.disease_cause Genomic Instability 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Ubiquitin Cell Line Tumor medicine Humans DNA Breaks Double-Stranded Homologous Recombination Papillomaviridae 030304 developmental biology 0303 health sciences Multidisciplinary Papillomavirus Infections DNA replication Cell biology Ubiquitin ligase PNAS Plus chemistry 030220 oncology & carcinogenesis Host-Pathogen Interactions biology.protein Female Tumor Suppressor p53-Binding Protein 1 Carcinogenesis DNA Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences. 116:19552-19562 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | High-risk human papillomaviruses (HR-HPVs) promote cervical cancer as well as a subset of anogenital and head and neck cancers. Due to their limited coding capacity, HPVs hijack the host cell’s DNA replication and repair machineries to replicate their own genomes. How this host–pathogen interaction contributes to genomic instability is unknown. Here, we report that HPV-infected cancer cells express high levels of RNF168, an E3 ubiquitin ligase that is critical for proper DNA repair following DNA double-strand breaks, and accumulate high numbers of 53BP1 nuclear bodies, a marker of genomic instability induced by replication stress. We describe a mechanism by which HPV E7 subverts the function of RNF168 at DNA double-strand breaks, providing a rationale for increased homology-directed recombination in E6/E7-expressing cervical cancer cells. By targeting a new regulatory domain of RNF168, E7 binds directly to the E3 ligase without affecting its enzymatic activity. As RNF168 knockdown impairs viral genome amplification in differentiated keratinocytes, we propose that E7 hijacks the E3 ligase to promote the viral replicative cycle. This study reveals a mechanism by which tumor viruses reshape the cellular response to DNA damage by manipulating RNF168-dependent ubiquitin signaling. Importantly, our findings reveal a pathway by which HPV may promote the genomic instability that drives oncogenesis. |
| Databáze: | OpenAIRE |
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