Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response
Menée in vitro, cette étude met en évidence un mécanisme par lequel l'oncoprotéine E7 du papillomavirus humain, en altérant la fonction de la ligase RNF 168, perturbe le mécanisme de réparation de l'ADN et favorise ainsi l'instabilité génomique de la cellule hôte
Human papillomaviruses (HPVs) cause 5% of all cancers, including cervical cancers and a growing number of oropharyngeal cancers, which are reaching epidemic proportion. While HPV oncogenes promote the acquisition of cancer hallmarks such as sustained proliferation and resistance to cell death by targeting the p53 and pRb pathways, the mechanism by which they induce genomic instability leading to cellular transformation remains largely unknown. This paper describes how the HPV oncoprotein E7 directly impedes the cellular response to DNA double-strand breaks by interacting with a previously uncharacterized domain of the E3 ubiquitin ligase RNF168. As the function of RNF168 is essential for proper DNA repair, our findings reveal a mechanism by which HPV induces genomic instability and fuels cancer progression.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.