HPV-18 E2 protein downregulates antisense noncoding mitochondrial RNA-2, delaying replicative senescence of human keratinocytes

Abstract

Human and mouse cells display a differential expression pattern of a family of mitochondrial noncoding RNAs (ncmtRNAs), according to proliferative status. Normal proliferating and cancer cells express a sense ncmtRNA (SncmtRNA), which seems to be required for cell proliferation, and two antisense transcripts referred to as ASncmtRNA-1 and -2. Remarkably however, the ASncmtRNAs are downregulated in human and mouse cancer cells, including HeLa and SiHa cells, transformed with HPV-18 and HPV-16, respectively. HPV E2 protein is considered a tumor suppressor in the context of high-risk HPV-induced transformation and therefore, to explore the mechanisms involved in the downregulation of ASncmtRNAs during tumorigenesis, we studied human foreskin keratinocytes (HFK) transduced with lentiviral-encoded HPV-18 E2. Transduced cells displayed a significantly extended replicative lifespan of up to 23 population doublings, compared to 8 in control cells, together with downregulation of the ASncmtRNAs. At 26 population doublings, cells transduced with E2 were arrested at G2/M, together with downregulation of E2 and SncmtRNA and upregulation of ASncmtRNA-2. Our results suggest a role for high-risk HPV E2 protein in cellular immortalization. Additionally, we propose a new cellular phenotype according to the expression of the SncmtRNA and the ASncmtRNAs.

Inhibition of oxidative stress induced-cytotoxicity by coptisine in V79-4 Chinese hamster lung fibroblasts through the induction of Nrf-2 mediated HO-1 expression

“…Actin was utilized as an internal control, and the proteins were visualized using an ECL detection system is consistent with a previous finding (Kang et al 2005). In agreement with the results of previous studies (Villota et al 2018;Kim et al 2008;Seomun et al 2005), the upregulated expression of Cdk inhibitor p21 WAF1/CIP1 , and the downregulated expression of cyclin A and cyclin B1 were associated with the induction of G2/M arrest by H 2 O 2 . During the cell cycle, the transition from G2 to M phase requires increased Cdk2 and Cdk1 (also called cell division cycle 2, Cdc2) kinase activity by cyclin A and B-type cyclins complexing (Pei and Xiong 2005;Swanton 2004).…”

Interactomics: Dozens of Viruses, Co-evolving With Humans, Including the Influenza A Virus, may Actively Distort Human Aging

“…For instance, HPVs, in particular HPV16/18 use their viral oncoproteins E6 and E7 to manipulate host signaling pathways involved in cell proliferation, cell death, and innate immunity ( Lo Cigno et al 2020 ), depleting multiple innate immunity effectors. Moreover, HPV-18 protein E2 can delay replicative senescence of human keratinocytes by downregulating antisense noncoding mitochondrial RNA-2 ( Villota et al 2018 ). Consistently, HPV16/18 infections have been proposed to correlate with epigenetic age acceleration of cervical squamous cell carcinoma ( Lu et al 2020 ).…”

Human papillomavirus associated cervical lesion: pathogenesis and therapeutic interventions

“…However, the E2 protein can bind to P53, attenuating its ability to induce cellular senescence in response to DNA damage 167 . Notably, the HPV‐18 E2 protein can downregulate antisense noncoding mitochondrial RNA‐2, consequently delaying replicative senescence in HKs 168 …”