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Topoisomerase IIβ-binding protein 1 activates expression of E2F1 and p73 in HPV positive cells for genome amplification upon epithelial differentiation
- Source :
- Oncogene
- Publication Year :
- 2019
-
Abstract
- High-risk human papillomaviruses (HPVs) constitutively activate ataxia telangiectasia mutated (ATM) and ataxia telangiectasia- and Rad3-related (ATR) DNA damage repair pathways for viral genome amplification. HPVs activate these pathways through the immune regulator STAT-5. For the ATR pathway, STAT-5 increases expression of the topoisomerase IIβ-binding protein 1 (TopBP1), a scaffold protein that binds ATR and recruits it to sites of DNA damage. TopBP1 also acts as a transcriptional regulator, and we investigated how this activity influenced the HPV life cycle. We determined that TopBP1 levels are increased in cervical intraepithelial neoplasias as well as cervical carcinomas, consistent with studies in HPV-positive cell lines. Suppression of TopBP1 by shRNAs impairs HPV genome amplification and activation of the ATR pathway but does not affect the total levels of ATR and CHK1. In contrast, knockdown reduces the expression of other DNA damage factors such as RAD51 and Mre11 but not BRCA2 or NBS1. Interestingly, TopBP1 positively regulates the expression of E2F1, a TopBP1-binding partner, and p73 in HPV-positive cells in contrast to its effects in other cell types. TopBP1 transcriptional activity is regulated by AKT, and treatment with AKT inhibitors suppresses expression of E2F1 and p73 without interfering with ATR signaling. Importantly, the levels of p73 are elevated in HPV-positive cells and its knockdown impairs HPV genome amplification. This demonstrates that p73, like p63 and p53, is an important regulator of the HPV life cycle that is controlled by the transcriptional activating properties of the multifunctional TopBP1 protein.
- Subjects :
- 0301 basic medicine
Scaffold protein
Cancer Research
Transcription, Genetic
Regulator
Uterine Cervical Neoplasms
Ataxia Telangiectasia Mutated Proteins
Mice
0302 clinical medicine
Transcriptional regulation
STAT5 Transcription Factor
E2F1
Papillomaviridae
Gene knockdown
MRE11 Homologue Protein
Nuclear Proteins
Cell Differentiation
3. Good health
Cell biology
DNA-Binding Proteins
030220 oncology & carcinogenesis
Female
biological phenomena, cell phenomena, and immunity
Signal Transduction
DNA damage
Biology
Article
Cell Line
03 medical and health sciences
Genetics
medicine
Animals
Humans
Molecular Biology
Protein kinase B
Papillomavirus Infections
Gene Amplification
Epithelial Cells
Tumor Protein p73
medicine.disease
Uterine Cervical Dysplasia
030104 developmental biology
Gene Expression Regulation
Ataxia-telangiectasia
Checkpoint Kinase 1
NIH 3T3 Cells
Rad51 Recombinase
Carrier Proteins
E2F1 Transcription Factor
DNA Damage
Subjects
Details
- Language :
- English
- ISSN :
- 14765594 and 09509232
- Volume :
- 38
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....129c2dbceb561fd7eccb5e80d055861a