β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

Snow, Jazmine A.; Murthy, Vaibhav; Dacus, Dalton; Hu, Changkun; Wallace, Nicholas A.

doi:10.3390/pathogens8040267

Cited by 21 publications

(27 citation statements)

References 67 publications

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“…Recently, β-HPV E6 was also found to impair phosphorylation of Chk1. While this resulted in HR impairment, the mechanism that impaired ATR's ability to phosphorylate Chk1 remains unclear [40]. In the case of EBV, we have shown that active STAT3 transcriptionally upregulates the anti-apoptotic form of caspase 9 which then activates caspase 7 resulting in degradation of claspin, a key adaptor protein [9][10][11].…”

Section: Plos Pathogensmentioning

confidence: 99%

STAT3 imparts BRCAness by impairing homologous recombination repair in Epstein-Barr virus-transformed B lymphocytes

et al. 2020

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Epstein-Barr virus (EBV) causes lymphomas and epithelial cell cancers. Though generally silent in B lymphocytes, this widely prevalent virus can cause endemic Burkitt lymphoma and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. By learning how EBV breaches barriers to cell proliferation, we hope to undermine those strategies to treat EBV lymphomas and potentially other cancers. We had previously found that EBV, through activation of cellular STAT3 prevents phosphorylation of Chk1, and thereby, suppresses activation of the intra-S phase cell-cycle checkpoint, a potent barrier to oncogene-driven proliferation. This observation prompted us to examine the consequences on DNA repair since homologous recombination repair, the most error-free form, requires phosphoChk1. We now report that the defect in Chk1 phosphorylation also curtails RAD51 nucleation, and thereby, homologous recombination repair of DNA double strand breaks. The resulting reliance on error-prone microhomology-mediated end-joining (MMEJ) repair makes EBV-transformed cells susceptible to PARP inhibition and simultaneous accrual of genome-wide deletions and insertions resulting from synthesis-dependent MMEJ. Analysis of transcriptomic and drug susceptibility data from hundreds of cancer lines reveals a STAT3-dependent gene-set predictive of susceptibility of cancers to synthetic lethal PARP inhibition. These findings i) demonstrate how the tumor virus EBV reshapes cellular DNA

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Section: Plos Pathogensmentioning

confidence: 99%

STAT3 imparts BRCAness by impairing homologous recombination repair in Epstein-Barr virus-transformed B lymphocytes

et al. 2020

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“…Among β-HPV proteins, the E6 or β-HPV E6 is best characterized. This report focuses on the E6 from β-HPV 8 (β-HPV 8E6), and its ability to disrupt DNA repair [ 16 , 17 , 18 , 19 ]. Interestingly, β-HPV 8E6 exerts its influence in part by binding and destabilizing the cellular histone acetyltransferase, p300 [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Beta Human Papillomavirus 8E6 Attenuates Non-Homologous End Joining by Hindering DNA-PKcs Activity

Bugbee

Gamez

et al. 2020

Cancers

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Cutaneous viral infections occur in a background of near continual exposure to environmental genotoxins, like UV radiation in sunlight. Failure to repair damaged DNA is an established driver of tumorigenesis and substantial cellular resources are devoted to repairing DNA lesions. Beta-human papillomaviruses (β-HPVs) attenuate DNA repair signaling. However, their role in human disease is unclear. Some have proposed that β-HPV promotes tumorigenesis, while others suggest that β-HPV protects against skin cancer. Most of the molecular evidence that β-HPV impairs DNA repair has been gained via characterization of the E6 protein from β-HPV 8 (β-HPV 8E6). Moreover, β-HPV 8E6 hinders DNA repair by binding and destabilizing p300, a transcription factor for multiple DNA repair genes. By reducing p300 availability, β-HPV 8E6 attenuates a major double strand DNA break (DSB) repair pathway, homologous recombination. Here, β-HPV 8E6 impairs another DSB repair pathway, non-homologous end joining (NHEJ). Specifically, β-HPV 8E6 acts by attenuating DNA-dependent protein kinase (DNA-PK) activity, a critical NHEJ kinase. This includes DNA-PK activation and the downstream of steps in the pathway associated with DNA-PK activity. Notably, β-HPV 8E6 inhibits NHEJ through p300 dependent and independent means. Together, these data expand the known genome destabilizing capabilities of β-HPV 8E6.

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“…Animal models show that certain ␤-HPV E6 genes can contribute to UV-associated carcinogenesis (18,19,23). In vitro studies from our group and others have added molecular details by describing ␤-HPV E6's ability to impair the DDR by destabilizing p300 (18,22,27,28,35,36). Despite this focus on repair, there are DDR-independent pathways that protect genome fidelity (37)(38)(39).…”

Section: Resultsmentioning

confidence: 99%

Beta Human Papillomavirus 8E6 Attenuates LATS Phosphorylation after Failed Cytokinesis

Dacus

Cotton

McCallister

et al. 2020

J Virol

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Beta genus human papillomaviruses (β-HPVs) cause cutaneous squamous cell carcinomas (cSCCs) in a subset of immunocompromised patients. However, β-HPVs are not necessary for tumor maintenance in the general population. Instead, they may destabilize the genome in the early stages of cancer development. Supporting this idea, β-HPV’s 8E6 protein attenuates p53 accumulation after failed cytokinesis. This paper offers mechanistic insight into how β-HPV E6 causes this change in cell signaling. An in silico screen and characterization of HCT 116 cells lacking p300 suggested that the histone acetyltransferase is a negative regulator of Hippo pathway (HP) gene expression. HP activation restricts growth in response to stimuli, including failed cytokinesis. Loss of p300 resulted in increased HP gene expression, including proproliferative genes associated with HP inactivation. β-HPV 8E6 expression recapitulates some of these phenotypes. We used a chemical inhibitor of cytokinesis (dihydrocytochalasin B [H2CB]) to induce failed cytokinesis. This system allowed us to show that β-HPV 8E6 reduced activation of large tumor suppressor kinase (LATS), an HP kinase. LATS is required for p53 accumulation following failed cytokinesis. These phenotypes were dependent on β-HPV 8E6 destabilizing p300 and did not completely attenuate the HP. It did not alter H2CB-induced nuclear exclusion of the transcription factor YAP. β-HPV 8E6 also did not decrease HP activation in cells grown to a high density. Although our group and others have previously described inhibition of DNA repair, to the best of our knowledge, this marks the first time that a β-HPV E6 protein has been shown to hinder HP signaling. IMPORTANCE β-HPVs contribute to cSCC development in immunocompromised populations. However, it is unclear if these common cutaneous viruses are tumorigenic in the general population. Thus, a more thorough investigation of β-HPV biology is warranted. If β-HPV infections do promote cSCCs, they are hypothesized to destabilize the cellular genome. In vitro data support this idea by demonstrating the ability of the β-HPV E6 protein to disrupt DNA repair signaling events following UV exposure. We show that β-HPV E6 more broadly impairs cellular signaling, indicating that the viral protein dysregulates the HP. The HP protects genome fidelity by regulating cell growth and apoptosis in response to a myriad of deleterious stimuli, including failed cytokinesis. After failed cytokinesis, β-HPV 8E6 attenuates phosphorylation of the HP kinase (LATS). This decreases some, but not all, HP signaling events. Notably, β-HPV 8E6 does not limit senescence associated with failed cytokinesis.

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β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

Cited by 21 publications

References 67 publications

STAT3 imparts BRCAness by impairing homologous recombination repair in Epstein-Barr virus-transformed B lymphocytes

STAT3 imparts BRCAness by impairing homologous recombination repair in Epstein-Barr virus-transformed B lymphocytes

Beta Human Papillomavirus 8E6 Attenuates Non-Homologous End Joining by Hindering DNA-PKcs Activity

Beta Human Papillomavirus 8E6 Attenuates LATS Phosphorylation after Failed Cytokinesis

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