Telomeres and Telomerase During Human Papillomavirus-Induced Carcinogenesis

Anna Pańczyszyn, Ewa Boniewska-Bernacka, Grzegorz Głąb, Anna Pańczyszyn, Ewa Boniewska-Bernacka, Grzegorz Głąb

Abstract

Human papillomaviruses (HPVs) belong to a small spherical virus family and are transmitted through direct contact, most often through sexual behavior. More than 200 types of HPV are known, a dozen or so of which are classified as high-risk viruses (HR HPV) and may contribute to the development of cervical cancer. HPV is a small virus with a capsid composed of L1 and L2 proteins, which are crucial for entry to the cell. The infection begins at the basal cell layer and progresses to involve cells from higher layers of the cervical epithelium. E6 and E7 viral proteins are involved in the process of carcinogenesis. They interact with suppressors of oncogenesis, including p53 and Rb proteins. This leads to DNA replication and intensive cell divisions. The persistent HR HPV infection leads to the development of dysplasia and these changes may progress to invasive cancer. During the initial stage of carcinogenesis, telomeres shorten until telomerase activates. The activation of telomerase, the enzyme necessary to extend chromosome ends (telomeres) is the key step in cell immortalization. Analyzing the expression level of hTERT and hTERC genes encoding telomerase and telomere length measurement may constitute new markers of the early carcinogenesis.

Conflict of interest statement

Conflict of interest

Anna Pańczyszyn, Ewa Boniewska-Bernacka, and Grzegorz Głąb declare no conflicts of interest.

Funding

The article was funded from the internal grant of Department of Biotechnology and Molecular Biology, University of Opole, Opole, Poland.

Figures

Fig. 1
Fig. 1
Structure of human papillomavirus ( modified from Fernandes et al. [15])
Fig. 2
Fig. 2
Normal and infected epithelium. Human papillomavirus penetrates the mucosal epithelium via microinjuries. The infection begins with the basal cell layer and successively progresses to involve cells from higher layers. Expression of the human papillomavirus genes (E6 and E7) promotes uncontrolled cell proliferation. If the immune system does not eliminate viruses, a long period of infection may cause cancer development ( modified from Tomaić [24]). HPV human papillomavirus
Fig. 3
Fig. 3
Human papillomaviruses block apoptosis ( modified from Jayshree et al. [39]). Cdk4/6 and Cdk2 cyclin-dependent kinases, CycD cyclin D, E2F transcription factor, E6 and E7 human papillomavirus proteins, E6AP ubiquitin ligase, pRB retinoblastoma protein
Fig. 4
Fig. 4
Telomerase activation by human papillomavirus protein E6. E6/E6AP affects hTERT promoter repressors—USF1/2—which bind to cis elements of promotor (X1 boxes, E boxes, and GC-rich sequences) and NFX1-91, and recruits histone deacetylase (HDAC) through mSin3A. cMYC/Max heterodimer, Sp1, and histone acetyltransferases (HAT) bind to the hTERT promoter and activate hTERT expression. hTERT activation is also increased by NFX1-123 with cytoplasmic poly(A) binding proteins (PABPCs) which cooperate with E6/E6AP (modified from Howie et al. [31]). E6AP ubiquitin ligase

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