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Radiother Oncol. 2014 Dec;113(3):337-44. doi: 10.1016/j.radonc.2014.08.026. Epub 2014 Sep 9.

Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage.

Author information

1
McArdle Laboratory for Cancer Research and Department of Oncology, University of Wisconsin, Madison, USA.
2
Department of Human Oncology, University of Wisconsin, Madison, USA; University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, USA.
3
McArdle Laboratory for Cancer Research and Department of Oncology, University of Wisconsin, Madison, USA; University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, USA.
4
Department of Human Oncology, University of Wisconsin, Madison, USA; University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, USA. Electronic address: rkimple@humonc.wisc.edu.

Abstract

BACKGROUND AND PURPOSE:

Patients with human papillomavirus related (HPV+) head and neck cancers (HNCs) demonstrate improved clinical outcomes compared to traditional HPV negative (HPV-) HNC patients. We have recently shown that HPV+ HNC cells are more sensitive to radiation than HPV- HNC cells. However, roles of HPV oncogenes in regulating the response of DNA damage repair remain unknown.

MATERIAL AND METHODS:

Using immortalized normal oral epithelial cell lines, HPV+ HNC derived cell lines, and HPV16 E7-transgenic mice we assessed the repair of DNA damage using γ-H2AX foci, single and split dose clonogenic survival assays, and immunoblot. The ability of E7 to modulate expression of proteins associated with DNA repair pathways was assessed by immunoblot.

RESULTS:

HPV16 E7 increased retention of γ-H2AX nuclear foci and significantly decreased sublethal DNA damage repair. While phospho-ATM, phospho-ATR, Ku70, and Ku80 expressions were not altered by E7, Rad51 was induced by E7. Correspondingly, HPV+ HNC cell lines showed retention of Rad51 after γ-radiation.

CONCLUSIONS:

Our findings provide further understanding as to how HPV16 E7 manipulates cellular DNA damage responses that may underlie its oncogenic potential and influence the altered sensitivity to radiation seen in HPV+ HNC as compared to HPV- HNC.

KEYWORDS:

DNA damage repair; HPV-positive head and neck cancer; HPV16 E7

PMID:
25216575
PMCID:
PMC4268372
DOI:
10.1016/j.radonc.2014.08.026
[Indexed for MEDLINE]
Free PMC Article

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