High-Risk Human Papillomaviruses and DNA Repair

Mehta, Kavi P.M.; Laimins, Laimonis A.

doi:10.1007/978-3-030-57362-1_7

Cited by 8 publications

(9 citation statements)

References 73 publications

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“…High-risk HPV-types activate ATM and a considerable number of further DDR and DNA repair factors, which is a requirement for effective viral DNA replication during the normal viral life cycle. Amongst other mechanisms, a direct interaction of ATM and the HPV oncoprotein E7 has been described, but its contribution to ATM activation remains unclear (57)(58)(59). The discrepancy between an impaired DDR in HPV+ HNSCC cells after irradiation and the activation of the DDR by high-risk HPV during their normal life cycle may suggest that the activation is not so much a direct functional feature of the HPV oncoproteins but to a larger extent a consequence of the rapid and error-prone productive viral DNA replication process (60), which is usually lost in HPV+ malignancies.…”

Section: Discussionmentioning

confidence: 99%

A Lack of Effectiveness in the ATM-Orchestrated DNA Damage Response Contributes to the DNA Repair Defect of HPV-Positive Head and Neck Cancer Cells

et al. 2022

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Patients with human papillomavirus-positive squamous cell carcinoma of the head and neck (HPV+ HNSCC) have a favorable prognosis compared to those with HPV-negative (HPV−) ones. We have shown previously that HPV+ HNSCC cell lines are characterized by enhanced radiation sensitivity and impaired DNA double-strand break (DSB) repair. Since then, various publications have suggested a defect in homologous recombination (HR) and dysregulated expression of DSB repair proteins as underlying mechanisms, but conclusions were often based on very few cell lines. When comparing the expression levels of suggested proteins and other key repair factors in 6 HPV+ vs. 5 HPV− HNSCC strains, we could not confirm most of the published differences. Furthermore, HPV+ HNSCC strains did not demonstrate enhanced sensitivity towards PARP inhibition, questioning a general HR defect. Interestingly, our expression screen revealed minimal levels of the central DNA damage response kinase ATM in the two most radiosensitive HPV+ strains. We therefore tested whether insufficient ATM activity may contribute to the enhanced cellular radiosensitivity. Irrespective of their ATM expression level, radiosensitive HPV+ HNSCC cells displayed DSB repair kinetics similar to ATM-deficient cells. Upon ATM inhibition, HPV+ cell lines showed only a marginal increase in residual radiation-induced γH2AX foci and induction of G2 cell cycle arrest as compared to HPV− ones. In line with these observations, ATM inhibition sensitized HPV+ HNSCC strains less towards radiation than HPV− strains, resulting in similar levels of sensitivity. Unexpectedly, assessment of the phosphorylation kinetics of the ATM targets KAP-1 and Chk2 as well as ATM autophosphorylation after radiation did not indicate directly compromised ATM activity in HPV-positive cells. Furthermore, ATM inhibition delayed radiation induced DNA end resection in both HPV+ and HPV− cells to a similar extent, further suggesting comparable functionality. In conclusion, DNA repair kinetics and a reduced effectiveness of ATM inhibition clearly point to an impaired ATM-orchestrated DNA damage response in HPV+ HNSCC cells, but since ATM itself is apparently functional, the molecular mechanisms need to be further explored.

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Section: Discussionmentioning

confidence: 99%

A Lack of Effectiveness in the ATM-Orchestrated DNA Damage Response Contributes to the DNA Repair Defect of HPV-Positive Head and Neck Cancer Cells

et al. 2022

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“…Interestingly, a correlation between HPV16 integration sites and CTCF binding sites in the host genome has been established [31], and interaction between SMC1A and ChlR1, a known tethering factor of HPV genomes is known to occur [36,37]; whether this association of CTCF and integration sites occurs due to previous tethering here is unknown. Furthermore, disruption of SMC1A and/or CTCF in HPV31 carrying CIN-612 cells and subsequent loss of genomes has also been hypothesised to be related to disruption of HPV infection mediated activation of the ataxia telangiectasia mutated-dependent (ATM) DNA damage response and the ataxia telangiectasia mutated-dependent DNA-related (ATR) pathway [15,38,39]. Here, SMC1A recruits DNA damage binding proteins to replicating virus genomes to maintain orderly replication, which could be dependent on initial CTCF binding of HPV sequences.…”

Section: Discussionmentioning

confidence: 99%

CTCF association with episomal HPV16 genomes regulates viral oncogene transcription and splicing

Groves

Tang

Pentland

et al. 2021

Preprint

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Human papillomavirus 16 (HPV16) is a high-risk alphapapillomavirus that is associated with cancers of mucosal epithelia. The virus genome exists in cells as an episome but can integrate and overexpress the E6 and E7 viral oncogenes. In related high-risk family members HPV18 and HPV31, host proteins including CTCF, an insulator, and SMC1A, a component of the cohesion complex, are known to interact with the viral genome and alter transcriptional activity, splicing patterns and episome amplification. However, the roles of these two proteins during HPV16 infection has not yet been fully examined. Here, we show during differentiation of the episomal HPV16-containing W12 cell line that CTCF association increases with the virus genome at the known E2 binding site, whilst additional CTCF binding now occurs at the putative L2 binding site, with SMC1A association occurring unchanged here. While expression of virus late transcripts (E4^L1, L2, L1) is stimulated, early transcript levels decrease by 48 hours, with the exception of the E6*IV spliced transcript. Conversely, in undifferentiated, monolayer W12 cells, CTCF knockdown increases the level of all early transcripts, whereas E6*IV level increases. Additionally, CTCF ablation as well as SMC1A knockdown results in decreases to HPV16 genome copy number. Taken together, this supports the model that while CTCF and SMC1A have a role in HPV16 genome maintenance, CTCF plays a greater part in regulating HPV16 oncogene splicing and expression during the natural lifecycle of the virus, and may be involved in a reduced risk of cancer development during episomal HPV16 infections.

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“…Ethanol also induces a DNA damage response [91]. The other primary risk factor for oropharyngeal tumors is HPV infection; the viral proteins E1/E2 activate ATM and ATR [92], and E6 and E7 proteins inhibit the cell cycle checkpoints p53 and pRB, respectively.…”

Section: Responsementioning

confidence: 99%

A Review of the Repair of DNA Double Strand Breaks in the Development of Oral Cancer

Prime,

Darski,

Hunter

et al. 2024

IJMS

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We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders (OPMD) to undergo malignant transformation to oral squamous cell carcinoma (OSCC). Defects in the homologous recombination/Fanconi anemia (HR/FA), but not in the non-homologous end joining, causes the DNA repair pathway to appear to be consistent with features of familial conditions that are predisposed to OSCC (FA, Bloom’s syndrome, Ataxia Telangiectasia); this is true for OSCC that occurs in young patients, sometimes with little/no exposure to classical risk factors. Even in Dyskeratosis Congenita, a disorder of the telomerase complex that is also predisposed to OSCC, attempts at maintaining telomere length involve a pathway with shared HR genes. Defects in the HR/FA pathway therefore appear to be pivotal in conditions that are predisposed to OSCC. There is also some evidence that abnormalities in the HR/FA pathway are associated with malignant transformation of sporadic cases OPMD and OSCC. We provide data showing overexpression of HR/FA genes in a cell-cycle-dependent manner in a series of OPMD-derived immortal keratinocyte cell lines compared to their mortal counterparts. The observations in this study argue strongly for an important role of the HA/FA DNA repair pathway in the development of OSCC.

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High-Risk Human Papillomaviruses and DNA Repair

Cited by 8 publications

References 73 publications

A Lack of Effectiveness in the ATM-Orchestrated DNA Damage Response Contributes to the DNA Repair Defect of HPV-Positive Head and Neck Cancer Cells

A Lack of Effectiveness in the ATM-Orchestrated DNA Damage Response Contributes to the DNA Repair Defect of HPV-Positive Head and Neck Cancer Cells

CTCF association with episomal HPV16 genomes regulates viral oncogene transcription and splicing

A Review of the Repair of DNA Double Strand Breaks in the Development of Oral Cancer

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