A Critical Role for p53 during the HPV16 Life Cycle

Fontan, Christian T.; James, Claire D.; Prabhakar, Apurva T.; Bristol, Molly L.; Otoa, Raymonde; Wang, Xu; Karimi, Elmira; Rajagopalan, Padmavathy; Basu, Devraj; Morgan, Iain M.

doi:10.1128/spectrum.00681-22

Cited by 15 publications

(17 citation statements)

References 80 publications

(116 reference statements)

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“…p53 levels in HFK+HPV16 cells are detectable as E6 is spliced to E6* which removes the p53 degradation domain of E6 (28). We have demonstrated abundant p53 expression in HPV positive head and neck cancer cell lines and patient derived xenografts, as well as in primary keratinocytes immortalized by the entire HPV16 genome (29). No p53 is detectable in the HFK+E6E7 cells as E6 is not spliced and can therefore target p53 for proteasomal degradation.…”

Section: Resultsmentioning

confidence: 99%

“…E6 expression certainly degrades p53 but in cells immortalized by the full genome E6 can be spliced to E6* which removes the ability to degrade p53 (28). Recently we demonstrated robust p53 protein expression in HFK+HPV16, in HPV16 positive head and neck cancer cell lines, and in HPV16 positive head and neck cancer patient derived xenografts (29). Overexpression of full length E6 in HFK+HPV16 cells abrogated their growth (an E6 mutant unable to degrade p53 did not) suggesting that p53 may be important for the HPV16 life cycle.…”

Section: Discussionmentioning

confidence: 99%

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A human papillomavirus 16 E2-TopBP1 dependent SIRT1-p300 acetylation switch regulates mitotic viral and human protein levels

Prabhakar,

James,

Youssef

et al. 2024

Preprint

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An interaction between human papillomavirus 16 (HPV16) E2 and the cellular proteins TopBP1 and BRD4 is required for E2 plasmid segregation function. The E2-TopBP1 interaction promotes increased mitotic E2 protein levels in U2OS and N/Tert-1 cells, as well as in human foreskin keratinocytes immortalized by HPV16 (HFK+HPV16). SIRT1 deacetylation reduces E2 protein stability and here we demonstrate that increased E2 acetylation occurs during mitosis in a TopBP1 interacting dependent manner, promoting E2 mitotic stabilization. p300 mediates E2 acetylation and acetylation is increased due to E2 switching off SIRT1 function during mitosis in a TopBP1 interacting dependent manner, confirmed by increased p53 stability and acetylation on lysine 382, a known target for SIRT1 deacetylation. SIRT1 can complex with E2 in growing cells but is unable to do so during mitosis due to the E2-TopBP1 interaction; SIRT1 is also unable to complex with p53 in mitotic E2 wild type cells but can complex with p53 outside of mitosis. E2 lysines 111 and 112 are highly conserved residues across all E2 proteins and we demonstrate that K111 hyper-acetylation occurs during mitosis, promoting E2 interaction with Topoisomerase 1 (Top1). We also demonstrate that K112 ubiquitination promotes E2 proteasomal degradation during mitosis. The results present a model in which the E2-TopBP1 complex inactivates SIRT1 during mitosis and E2 acetylation on K111 by p300 increases, promoting interaction with Top1 that protects K112 from ubiquitination and therefore E2 proteasomal degradation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A human papillomavirus 16 E2-TopBP1 dependent SIRT1-p300 acetylation switch regulates mitotic viral and human protein levels

Prabhakar,

James,

Youssef

et al. 2024

Preprint

Self Cite

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“…[37][38] Indeed, among interaction with other viral proteins, p53 interacts with the C-terminal domain of E2 protein from high-risk HPVs. [20][21][22][39][40][41] Considering that the mechanism involved in the interplay between HPV E2 and p53 has not yet been elucidated, we decided to address the nature of the interaction between the two proteins, based on the initial mapping in transient transfection experiments. 21 We used the HPV16 C-terminal DNA-binding domain of E2 (E2C), and a rationally designed stability mutant of the full-length protein, previously described as pseudo wild-type p53.…”

Section: Resultsmentioning

confidence: 99%

“…19 Moreover, a very recent study showed that disruption of p53-HPV16 E2 interaction attenuates cell growth and blocks the viral life cycle. 40 Given p53 0 s features, its ability to undergo spontaneous LLPS is not surprising. These include modularity, oligomerization, nucleic acid between HPV E2 and p53 in the context of LLPS.…”

Section: Discussionmentioning

confidence: 99%

Biomolecular Condensation of the Human Papillomavirus E2 Master Regulator with P53: Implications in Viral Replication

Borkosky¹,

Fassolari²,

Campos-León

et al. 2022

SSRN Journal

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“…The results of this study represent one of likely many examples of a single virus targeting the same host molecule through multiple mechanisms. For example, Human Papillomavirus targets TP53 through independent mechanisms involving both the E6 and E7 proteins (Fontan et al, 2022). Likewise, poxviruses target caspase activity through multiple mechanisms (Nichols et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Human cytomegalovirus infection coopts chromatin organization to diminish TEAD1 transcription factor activity

Sayeed,

Parameswaran,

Beucler

et al. 2024

Preprint

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SummaryHuman cytomegalovirus (HCMV) infects up to 80% of the world’s population. Here, we show that HCMV infection leads to widespread changes in human chromatin accessibility and chromatin looping, with hundreds of thousands of genomic regions affected 48 hours after infection. Integrative analyses reveal HCMV-induced perturbation of Hippo signaling through drastic reduction of TEAD1 transcription factor activity. We confirm extensive concordant loss of TEAD1 binding, active H3K27ac histone marks, and chromatin looping interactions upon infection. Our data position TEAD1 at the top of a hierarchy involving multiple altered important developmental pathways. HCMV infection reduces TEAD1 activity through four distinct mechanisms: closing of TEAD1-bound chromatin, reduction of YAP1 and phosphorylated YAP1 levels, reduction of TEAD1 transcript and protein levels, and alteration ofTEAD1exon-6 usage. Altered TEAD1-based mechanisms are highly enriched at genetic risk loci associated with eye and ear development, providing mechanistic insight into HCMV’s established roles in these processes.

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A Critical Role for p53 during the HPV16 Life Cycle

Abstract: Human papillomaviruses are causative agents in around 5% of all cancers. There are currently no antivirals available to combat these infections and cancers, therefore it remains a priority to enhance our understanding of the HPV life cycle.

Cited by 15 publications

References 80 publications

A human papillomavirus 16 E2-TopBP1 dependent SIRT1-p300 acetylation switch regulates mitotic viral and human protein levels

A human papillomavirus 16 E2-TopBP1 dependent SIRT1-p300 acetylation switch regulates mitotic viral and human protein levels

Biomolecular Condensation of the Human Papillomavirus E2 Master Regulator with P53: Implications in Viral Replication

Human cytomegalovirus infection coopts chromatin organization to diminish TEAD1 transcription factor activity

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