# HPV Oncogenes Dysregulate Translesion Synthesis

> **NIH NIH R15** · KANSAS STATE UNIVERSITY · 2020 · $454,466

## Abstract

Cervical cancers (CaCxs) cause over 250,000 deaths annually are the result of human papillomavirus (HPV)
infections. The combination of low HPV vaccine uptake and the average time required for an HPV infection
(10-30 years) to cause a CaCx, mean that improving treatment options will remain essential for the foreseeable
future. CaCxs require continued HPV oncogene (HPV E6 and E7) expression for initiation and maintenance
making these viral oncogenes an attractive target for intervention. Because direct attacking HPV E6 and E7
remains technically difficult, we propose targeting their manipulation of cellular signaling. We identify
translesion synthesis (TLS) dysregulation in cervical cancers (CaCx) and show that HPV E6 and E7 cause this
aberrant signaling. TLS helps cells tolerate replication stress by preventing replication forks from stalling and
collapsing. It exchanges the high fidelity replicative polymerase for a TLS-polymerase (often POLη) that can
synthesize DNA with lower fidelity in adverse conditions. HPV E7 causes replication stress by allowing bypass
of G1/S-phase checkpoints and depleting nucleoside reserves. This activates TLS, but HPV E6 prevents
completion of the pathway by blocking POLη accumulation. We found both HPV oncogenes were capable of
preventing POLη induction in response to DNA damaging UV exposure. Both of these phenotypes correlate
with increased genome instability and sensitivity to exogenous replication stress (mitomycin C, cisplatin and
UV). Our overall hypothesis is that by taxing and inhibiting TLS HPV oncogenes impair genome fidelity
in cervical cancers. We test this hypothesis in two related, but distinct specific aims.
Aim 1 investigates the destabilizing created by HPV oncogene’s simultaneous activation and inhibition of TLS
using primary keratinocytes (the cell type HPV infects) that acutely or constitutively express HPV oncogenes.
The mutagenic consequences are defined using whole genome sequencing and established molecular
approaches, like immunofluorescence microscopy and immunoblotting.
Aim 2 determines the mechanism and consequences of the aberrant TLS response to cisplatin in CaCx. This
aim combines specialized approaches (e.g. visualization of metaphase chromosomes) and other molecular
techniques. It characterizes TLS in cells after UV and cisplatin exposure, defines the mechanism by which
HPV E6 and E7 prevent POLη induction in these cells, and examines the consequences of this TLS hindrance.
Undergraduate Student Involvement. Students are the bedrock of this proposal. They were instrumental in
generating the corroborative data and will continue to be integral in the proposed experiments. We anticipate
preparing 5 undergraduates for futures in research.

## Key facts

- **NIH application ID:** 9964440
- **Project number:** 1R15CA242057-01A1
- **Recipient organization:** KANSAS STATE UNIVERSITY
- **Principal Investigator:** Nicholas A Wallace
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $454,466
- **Award type:** 1
- **Project period:** 2020-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9964440

## Citation

> US National Institutes of Health, RePORTER application 9964440, HPV Oncogenes Dysregulate Translesion Synthesis (1R15CA242057-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9964440. Licensed CC0.

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