Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response.
Cell Line, Tumor
DNA Breaks, Double-Stranded
DNA Repair
Female
Genomic Instability
Homologous Recombination
Host-Pathogen Interactions
Humans
Papillomaviridae
/ metabolism
Papillomavirus E7 Proteins
/ genetics
Papillomavirus Infections
/ genetics
Signal Transduction
Tumor Suppressor p53-Binding Protein 1
/ metabolism
Ubiquitin
/ genetics
Ubiquitin-Protein Ligases
/ genetics
Uterine Cervical Neoplasms
/ virology
53BP1 nuclear bodies
DNA double-strand break
E7 protein
RNF168
high-risk human papillomavirus
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
24 09 2019
24 09 2019
Historique:
pmc-release:
09
03
2020
pubmed:
11
9
2019
medline:
22
4
2020
entrez:
11
9
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31501315
pii: 1906102116
doi: 10.1073/pnas.1906102116
pmc: PMC6765264
doi:
Substances chimiques
Papillomavirus E7 Proteins
0
TP53BP1 protein, human
0
Tumor Suppressor p53-Binding Protein 1
0
Ubiquitin
0
RNF168 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
19552-19562Subventions
Organisme : NCI NIH HHS
ID : R01 CA181581
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA226523
Pays : United States
Organisme : CIHR
ID : 152948
Pays : Canada
Organisme : CIHR
ID : 142491
Pays : Canada
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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