The DNA damage response activates HPV16 late gene expression at the level of RNA processing

Nilsson, Kjell; Wu, Chengjun; Kajitani, Naoko; Yu, Haoran; Tsimtsirakis, Efthymios; Gong, Lei; Winquist, Ellenor Backström; Glahder, Jacob; Ekblad, Lars; Wennerberg, Johan; Schwartz, Stefan

doi:10.1093/nar/gky227

Cited by 27 publications

(51 citation statements)

References 59 publications

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“…Furthermore, it has been recently shown that the cellular DDR interacts with RNA processing factors [ 57 , 58 , 59 , 60 ] and that the cellular DDR affects alternative splicing of cellular mRNAs [ 61 , 62 , 63 , 64 ]. To test the idea that the DDR contributes to HPV late gene expression, we used reporter cell line C33A2 that is designed to study induction of HPV16 late gene expression to investigate if the DNA damage response could activate HPV16 late gene expression [ 53 , 65 , 66 ]. Addition of the DNA damaging agent melphalan to this reporter cell line efficiently induced the DNA damage response in the C33A2 cells, and efficiently activated the HPV16 late L1 and L2 gene expression [ 66 ].…”

Section: Human Papillomavirus (Hpv) and The Cellular Dna Damage Rementioning

confidence: 99%

“…To test the idea that the DDR contributes to HPV late gene expression, we used reporter cell line C33A2 that is designed to study induction of HPV16 late gene expression to investigate if the DNA damage response could activate HPV16 late gene expression [ 53 , 65 , 66 ]. Addition of the DNA damaging agent melphalan to this reporter cell line efficiently induced the DNA damage response in the C33A2 cells, and efficiently activated the HPV16 late L1 and L2 gene expression [ 66 ]. We observed a several hundred-fold induction of HPV16 L1 and L2 mRNAs as a result of inhibition of HPV16 early polyadenylation and activation of HPV16 L1 mRNA splicing, while the effect at the level of transcription was relatively modest [ 66 ].…”

Section: Human Papillomavirus (Hpv) and The Cellular Dna Damage Rementioning

confidence: 99%

“…Addition of the DNA damaging agent melphalan to this reporter cell line efficiently induced the DNA damage response in the C33A2 cells, and efficiently activated the HPV16 late L1 and L2 gene expression [ 66 ]. We observed a several hundred-fold induction of HPV16 L1 and L2 mRNAs as a result of inhibition of HPV16 early polyadenylation and activation of HPV16 L1 mRNA splicing, while the effect at the level of transcription was relatively modest [ 66 ]. Figure 4 shows the striking shift from early polyA site usage in HPV16 to primarily late polyA signal usage in response to induction of the DDR ( Figure 4 ).…”

Section: Human Papillomavirus (Hpv) and The Cellular Dna Damage Rementioning

confidence: 99%

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Role of the DNA Damage Response in Human Papillomavirus RNA Splicing and Polyadenylation

Nilsson

Schwartz

2018

IJMS

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Human papillomaviruses (HPVs) have evolved to use the DNA repair machinery to replicate its DNA genome in differentiated cells. HPV activates the DNA damage response (DDR) in infected cells. Cellular DDR factors are recruited to the HPV DNA genome and position the cellular DNA polymerase on the HPV DNA and progeny genomes are synthesized. Following HPV DNA replication, HPV late gene expression is activated. Recent research has shown that the DDR factors also interact with RNA binding proteins and affects RNA processing. DDR factors activated by DNA damage and that associate with HPV DNA can recruit splicing factors and RNA binding proteins to the HPV DNA and induce HPV late gene expression. This induction is the result of altered alternative polyadenylation and splicing of HPV messenger RNA (mRNA). HPV uses the DDR machinery to replicate its DNA genome and to activate HPV late gene expression at the level of RNA processing.

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Section: Human Papillomavirus (Hpv) and The Cellular Dna Damage Rementioning

confidence: 99%

Section: Human Papillomavirus (Hpv) and The Cellular Dna Damage Rementioning

confidence: 99%

Section: Human Papillomavirus (Hpv) and The Cellular Dna Damage Rementioning

confidence: 99%

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Role of the DNA Damage Response in Human Papillomavirus RNA Splicing and Polyadenylation

Nilsson

Schwartz

2018

IJMS

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“…ATM has been shown to inhibit the demethylase KDM2A, which removes di-methyl groups from H3K36, and also negatively impacts KDM4A levels through proteasome-dependent degradation [ 65 , 66 ]. Interestingly, a recent study using integrated subgenomic HPV16 reporters demonstrated that exogenously-induced DNA damage leads to production of spliced late L1 mRNAs, specifically the E1^E4^L1RNA, in an ATM-dependent manner [ 67 ]. ATM activation is required for productive replication of HPV31 [ 27 ], though whether ATM contributes to the viral life cycle through epigenetic modifications on viral chromatin is unknown.…”

Section: Resultsmentioning

confidence: 99%

“…ATM has been recently shown to affect the splicing of late mRNAs expressed from integrated HPV16 subgenomic reporter plasmids, which is postulated to occur through phosphorylation of BRCA1 and the recruitment of splicing factors to viral RNAs [ 67 ]. Our studies suggest that ATM activity regulates splicing of late L1 RNAs expressed from HPV31 episomes through the maintenance of H3K36me3 on viral chromatin.…”

Section: Discussionmentioning

confidence: 99%

SETD2-dependent H3K36me3 plays a critical role in epigenetic regulation of the HPV31 life cycle

et al. 2018

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The life cycle of HPV is tied to the differentiation status of its host cell, with productive replication, late gene expression and virion production restricted to the uppermost layers of the stratified epithelium. HPV DNA is histone-associated, exhibiting a chromatin structure similar to that of the host chromosome. Although HPV chromatin is subject to histone post-translational modifications, how the viral life cycle is epigenetically regulated is not well understood. SETD2 is a histone methyltransferase that places the trimethyl mark on H3K36 (H3K36me3), a mark of active transcription. Here, we define a role for SETD2 and H3K36me3 in the viral life cycle. We have found that HPV positive cells exhibit increased levels of SETD2, with SETD2 depletion leading to defects in productive viral replication and splicing of late viral RNAs. Reducing H3K36me3 by overexpression of KDM4A, an H3K36me3 demethylase, or an H3.3K36M transgene also blocks productive viral replication, indicating a significant role for this histone modification in facilitating viral processes. H3K36me3 is enriched on the 3’ end of the early region of the high-risk HPV31 genome in a SETD2-dependent manner, suggesting that SETD2 may regulate the viral life cycle through the recruitment of H3K36me3 readers to viral DNA. Intriguingly, we have found that activation of the ATM DNA damage kinase, which is required for productive viral replication, is necessary for the maintenance of H3K36me3 on viral chromatin and for processing of late viral RNAs. Additionally, we have found that the HPV31 E7 protein maintains the increased SETD2 levels in infected cells through an extension of protein half-life. Collectively, our findings highlight the importance of epigenetic modifications in driving the viral life cycle and identify a novel role for E7 as well as the DNA damage response in the regulation of viral processes through epigenetic modifications.

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The human papillomavirus late life cycle and links to keratinocyte differentiation

Kirk,

Graham

2024

Journal of Medical Virology

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Regulation of human papillomavirus (HPV) gene expression is tightly linked to differentiation of the keratinocytes the virus infects. HPV late gene expression is confined to the cells in the upper layers of the epithelium where the virus capsid proteins are synthesized. As these proteins are highly immunogenic, and the upper epithelium is an immune‐privileged site, this spatial restriction aids immune evasion. Many decades of work have contributed to the current understanding of how this restriction occurs at a molecular level. This review will examine what is known about late gene expression in HPV‐infected lesions and will dissect the intricacies of late gene regulation. Future directions for novel antiviral approaches will be highlighted.

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The DNA damage response activates HPV16 late gene expression at the level of RNA processing

Cited by 27 publications

References 59 publications

Role of the DNA Damage Response in Human Papillomavirus RNA Splicing and Polyadenylation

Role of the DNA Damage Response in Human Papillomavirus RNA Splicing and Polyadenylation

SETD2-dependent H3K36me3 plays a critical role in epigenetic regulation of the HPV31 life cycle

The human papillomavirus late life cycle and links to keratinocyte differentiation

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