High Risk α-HPV E6 Impairs Translesion Synthesis by Blocking POLη Induction

Wendel, Sebastian O.; Snow, Jazmine A.; Bastian, Tyler; Brown, Laura; Hernandez, Candy; Burghardt, Emily; Kahn, Andrew; Murthy, Vaibhav; Neill, Daniel; Smith, Zachary C; Ault, Kevin A.; Tawfik, Ossama; Wu, Cen; Wallace, Nicholas A.

doi:10.3390/cancers13010028

Cited by 8 publications

(37 citation statements)

References 69 publications

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“…We have previously reported that the expression of TLS genes is often increased in cervical cancers (Wendel et al, 2021). To understand the extent that this increased expression occurred more or less frequently than in other cancers, we compared TLS gene expression across 16 tumor types found in the TCGA database(Cancer Genome Atlas Research Network et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

“…However, the extent that cells respond to HPV16 E7-associated replication stress by increasing TLS activity is unclear. We have shown that TLS gene expression is often elevated in cervical cancers (Wendel et al, 2021). Given that TLS responds to replication stress and that replication stress is common in tumors, it is not surprising that these genes are highly expressed in cervical cancer.…”

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confidence: 93%

“…This provides some speci city for targeting tumor cells that are less likely to pause cell cycle progression to address the DNA lesion. We recently demonstrated in vitro that cervical cancer cells can acquire cisplatin resistance by increasing the expression of polymerases involved in the translesion synthesis or TLS pathway (Ghosal and Chen, 2013; Ler and Carty, 2021;Wendel et al, 2021). These TLS polymerases let cells tolerate higher concentrations of cisplatin by allowing replication forks to bypass cisplatin-induced DNA lesions and thus avoid cisplatin-induced replication stress.…”

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confidence: 99%

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HPV 16 E7 Alters Translesion Synthesis Signaling

Wendel

Stoltz

et al. 2022

Preprint

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A subset of human papillomaviruses (HPVs) are the cause of virtually every cervical cancer. These so called “high risk” HPVs two major oncogenes (HPV E6 and E7) that are necessary for transformation. Among "high risk” HPVs, HPV16 causes most cervical cancers and is often used as a representative model for oncogenic HPVs. HPV16 E7 facilitates the vial lifecycle by the binding and destabilizing RB, which ensures the virus has access to cellular replication machinery. RB destabilization increases E2F1-responsive gene expression and causes replication stress. While HPV16 E6 mitigates some of the deleterious effects associated with this replication stress by degrading p53, cells undergo separate adaptations to tolerate the stress. Here, we demonstrate that this includes the activation of the translesion synthesis (TLS) pathway, which prevents replication stress from causing replication fork collapse. We show that significantly elevated TLS gene expression is more common in cervical cancers than 14 out of 15 the other cancer types that we analyzed. In addition to increased TLS protein abundance, HPV16 E7 expressing cells have a reduced ability to induct a critical TLS factor (POLη) in response to replication stress inducing agents. Finally, we show that increased expression of at least one TLS gene is associated with improved survival for women with cervical cancer.

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confidence: 99%

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confidence: 93%

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confidence: 99%

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HPV 16 E7 Alters Translesion Synthesis Signaling

Wendel

Stoltz

et al. 2022

Preprint

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“…To determine the expression pattern of NFX1-123-regulated genes across cervical cancer development, we analyzed a previously described dataset [ 23 ] by merging transcriptomic analyses from five datasets in the National Center for Biotechnology Information Gene Expression Omnibus or NCBI GEO (GSE145976) that contained transcriptomic data linked with disease progression information [ 26 ]. This combined dataset has transcriptomic data for 262 cervical tissues including: tissue with no evidence of disease (NED, n = 89), premalignant lesions (CIN1 = 89, CIN2 = 22, CIN3 = 47), and cervical cancers (Stage 1 = 25, Stage 2 = 44, Stage 3 = 11).…”

Section: Resultsmentioning

confidence: 99%

“…Least absolute shrinkage and selection operator (LASSO) and ranked stability selection was used to determine promising candidates correlating with cervical cancer disease progression from a pool of nineteen NFX1-123 responsive genes (TGM1, FBN2, HSPB1P1, PPL, SLPI, FOXA2, BNIPL, CCNB1IP1, IMPA2, RPS29, KRT16, RAET1G, LCE2B, LCE1B, ALDH3B2, NOTCH1, SPRR2G, CEBPD, LOR). The disease stage dependent gene expression data for LASSO variable selection stem from GSE145976 [ 26 ]. The LASSO computation was conducted using the GLMnet package in R-software.…”

Section: Methodsmentioning

confidence: 99%

Cervical Cancer Development: Implications of HPV16 E6E7-NFX1-123 Regulated Genes

Quist

Solorzano

Wendel

et al. 2021

Cancers

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High-risk human papillomavirus (HR HPV) causes nearly all cervical cancers, half of which are due to HPV type 16 (HPV16). HPV16 oncoprotein E6 (16E6) binds to NFX1-123, and dysregulates gene expression, but their clinical implications are unknown. Additionally, HPV16 E7’s role has not been studied in concert with NFX1-123 and 16E6. HR HPVs express both oncogenes, and transformation requires their expression, so we sought to investigate the effect of E7 on gene expression. This study’s goal was to define gene expression profiles across cervical precancer and cancer stages, identify genes correlating with disease progression, assess patient survival, and validate findings in cell models. We analyzed NCBI GEO datasets containing transcriptomic data linked with cervical cancer stage and utilized LASSO analysis to identify cancer-driving genes. Keratinocytes expressing 16E6 and 16E7 (16E6E7) and exogenous NFX1-123 were tested for LASSO-identified gene expression. Ten out of nineteen genes correlated with disease progression, including CEBPD, NOTCH1, and KRT16, and affected survival. 16E6E7 in keratinocytes increased CEBPD, KRT16, and SLPI, and decreased NOTCH1. Exogenous NFX1-123 in 16E6E7 keratinocytes resulted in significantly increased CEBPD and NOTCH1, and reduced SLPI. This work demonstrates the clinical relevance of CEBPD, NOTCH1, KRT16, and SLPI, and shows the regulatory effects of 16E6E7 and NFX1-123.

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The potential of PCNA inhibition as a therapeutic strategy in cervical cancer

Wendel,

Snow,

et al. 2023

Journal of Medical Virology

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Cervical cancers are the fourth most common and most deadly cancer in women worldwide. Despite being a tremendous public health burden, few novel approaches to improve care for these malignancies have been introduced. We discuss the potential for proliferating cell nuclear antigen (PCNA) inhibition to address this need as well as the advantages and disadvantages for compounds that can therapeutically inhibit PCNA with a specific focus on cervical cancer.

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High Risk α-HPV E6 Impairs Translesion Synthesis by Blocking POLη Induction

Cited by 8 publications

References 69 publications

HPV 16 E7 Alters Translesion Synthesis Signaling

HPV 16 E7 Alters Translesion Synthesis Signaling

Cervical Cancer Development: Implications of HPV16 E6E7-NFX1-123 Regulated Genes

The potential of PCNA inhibition as a therapeutic strategy in cervical cancer

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