CRISPR/Cas9-based inactivation of human papillomavirus oncogenes E6 or E7 induces senescence in cervical cancer cells

Inturi, Raviteja; Jemth, Per

doi:10.1016/j.virol.2021.07.005

Cited by 20 publications

(11 citation statements)

References 48 publications

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“…This has been shown for the GAM1 protein from a fowl adenovirus, for example, or human papillomavirus (HPV) E6 [ 61 , 62 ]. We, therefore, investigated if E4orf6 specifically reduces E1B-55K SUMOylation and verified the observation that E4orf6 deletion results in increased E1B-55K SUMOylation in H1299 cells, as HeLa cells express HPV E6 and E7 ( Figure S3 ) [ 63 ]. Next, we compared E4orf6-dependent E1B-55K SUMOylation with SUMOylation of the HAdV-C5 protein E2A as a representative SUMO target that does not interact with E4orf6 ( Figure 2 ) [ 39 ].…”

Section: Discussionmentioning

confidence: 77%

Protein–Protein Interactions Facilitate E4orf6-Dependent Regulation of E1B-55K SUMOylation in HAdV-C5 Infection

Fiedler

Hofmann-Sieber

et al. 2022

Viruses

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The human adenovirus type C5 (HAdV-C5) E1B-55K protein is a multifunctional regulator of HAdV-C5 replication, participating in many processes required for maximal virus production. Its multifunctional properties are primarily regulated by post-translational modifications (PTMs). The most influential E1B-55K PTMs are phosphorylation at highly conserved serine and threonine residues at the C-terminus, and SUMO conjugation to lysines 104 (K104) and 101 (K101) situated in the N-terminal region of the protein, which have been shown to regulate each other. Reversible SUMO conjugation provides a molecular switch that controls key functions of the viral protein, including intracellular trafficking and viral immune evasion. Interestingly, SUMOylation at SUMO conjugation site (SCS) K104 is negatively regulated by another multifunctional HAdV-C5 protein, E4orf6, which is known to form a complex with E1B-55K. To further evaluate the role of E4orf6 in the regulation of SUMO conjugation to E1B-55K, we analyzed different virus mutants expressing E1B-55K proteins with amino acid exchanges in both SCS (K101 and K104) in the presence or absence of E4orf6. We could exclude phosphorylation as factor for E4orf6-mediated reduction of E1B-55K SUMOylation. In fact, we demonstrate that a direct interaction between E1B-55K and E4orf6 is required to reduce E1B-55K SUMOylation. Additionally, we show that an E4orf6-mediated decrease of SUMO conjugation to K101 and K104 result in impaired co-localization of E1B-55K and SUMO in viral replication compartments. These findings indicate that E4orf6 inhibits E1B-55K SUMOylation, which could favor assembly of E4orf6-dependent E3 ubiquitin ligase complexes that are known to degrade a variety of host restriction factors by proteasomal degradation and, thereby, promote viral replication.

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Section: Discussionmentioning

confidence: 77%

Protein–Protein Interactions Facilitate E4orf6-Dependent Regulation of E1B-55K SUMOylation in HAdV-C5 Infection

Fiedler

Hofmann-Sieber

et al. 2022

Viruses

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“…Immunofluorescence microscopy was performed as described previously ( Inturi and Jemth, 2021 ). In brief, HeLa (CCL-2) cell lines obtained from American Type Culture Collection were cultured in DMEM supplemented with 10% (v/v) heat-inactivated fetal bovine serum and 1% (v/v) penicillin G and streptomycin sulfate solution (Gibco) at 37°C, 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Determinants of affinity, specificity, and phase separation in a supramodule from Post-synaptic density protein 95

Laursen¹,

Inturi²,

Østergaard³

et al. 2022

iScience

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“…Like other viruses, latency and dormancy account for the main bottleneck making it extremely difficult to eliminate a viral genome from the infected cells and achieve a satisfactory cure ( Chen et al., 2018 ; Lee, 2019 ). Numerous studies have been conducted to investigate the role of the CRISPR/Cas9 system in fighting against the HPV genome ( Tommasino, 2014 ; Zhen et al., 2016 ; Zhen and Li, 2017 ; Aghamiri et al., 2020 ; Gao et al., 2021 ; Inturi and Jemth, 2021 ; Najafi et al., 2022 ). Two HPV viral genes were identified as oncogenes that exhibit fundamental roles in deriving malignant cellular transformation, E6 and E7, specifically cervical carcinomas.…”

Section: Applications Of Crispr/cas Technology In Targeting Viral And...mentioning

confidence: 99%

“…Furthermore, CRISPR/Cas9 system was found to trigger cellular senescence in the Hela cells immortalized with HPV-18 by knocking down the expression of E6/E7 oncogenes. E6/E7-inhibited Hela cells manifested with increased β-galactosidase level, loss of lamin B1, and activation of p53/p21 and pRb/p21pathway ( Inturi and Jemth, 2021 ). The ability of the CRISPR/Cas9 system was further investigated in cervical cancer/pre-cancer cell lines and animal models by Gao et al.…”

Section: Applications Of Crispr/cas Technology In Targeting Viral And...mentioning

confidence: 99%

The State-of-the-Art of Gene Editing and its Application to Viral Infections and Diseases Including COVID-19

Hawsawi

Shams

Theyab

et al. 2022

Front. Cell. Infect. Microbiol.

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Gene therapy delivers a promising hope to cure many diseases and defects. The discovery of gene-editing technology fueled the world with valuable tools that have been employed in various domains of science, medicine, and biotechnology. Multiple means of gene editing have been established, including CRISPR/Cas, ZFNs, and TALENs. These strategies are believed to help understand the biological mechanisms of disease progression. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been designated the causative virus for coronavirus disease 2019 (COVID-19) that emerged at the end of 2019. This viral infection is a highly pathogenic and transmissible disease that caused a public health pandemic. As gene editing tools have shown great success in multiple scientific and medical areas, they could eventually contribute to discovering novel therapeutic and diagnostic strategies to battle the COVID-19 pandemic disease. This review aims to briefly highlight the history and some of the recent advancements of gene editing technologies. After that, we will describe various biological features of the CRISPR-Cas9 system and its diverse implications in treating different infectious diseases, both viral and non-viral. Finally, we will present current and future advancements in combating COVID-19 with a potential contribution of the CRISPR system as an antiviral modality in this battle.

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CRISPR/Cas9-based inactivation of human papillomavirus oncogenes E6 or E7 induces senescence in cervical cancer cells

Cited by 20 publications

References 48 publications

Protein–Protein Interactions Facilitate E4orf6-Dependent Regulation of E1B-55K SUMOylation in HAdV-C5 Infection

Protein–Protein Interactions Facilitate E4orf6-Dependent Regulation of E1B-55K SUMOylation in HAdV-C5 Infection

Determinants of affinity, specificity, and phase separation in a supramodule from Post-synaptic density protein 95

The State-of-the-Art of Gene Editing and its Application to Viral Infections and Diseases Including COVID-19

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