The Role of the DNA Damage Response throughout the  Papillomavirus Life Cycle

McKinney, Caleb; Hussmann, Katherine L.; McBride, Alison A.

doi:10.3390/v7052450

Cited by 69 publications

(73 citation statements)

References 120 publications

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“…Once entered the nucleus, HPV replicates to a low copy number (10–200 copy number/cell) during the initial amplification and establishment of infection [23]. As the proliferating cells (harboring HPV genomes) undergo transition through differentiation, the mode of viral genome replication switches to support productive viral genome amplification concomitant with increased levels of the E1 and E2 replication proteins [24]. In the terminally differentiated layer of epithelium L1 and L2 capsid proteins are expressed and viral particles are assembled.…”

Section: Entry Of Hpv and Life Cycle In Cervical Epithelial Cellmentioning

confidence: 99%

Molecular mechanisms of HPV mediated neoplastic progression

Senapati¹,

Senapati²,

Dwibedi³

2016

Infect Agents Cancer

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Human Papillomavirus is the major etiological agent in the development of cervical cancer but not a sufficient cause. Despite significant research, the underlying mechanisms of progression from a low-grade squamous intraepithelial lesion to high grade squamous intraepithelial lesion are yet to be understood. Deregulation of viral gene expression and host genomic instability play a central role in virus-mediated carcinogenesis. Key events such as viral integration and epigenetic modifications may lead to the deregulation of viral and host gene expression. This review has summarized the available literature to describe the possible mechanism and role of viral integration in mediating carcinogenesis. HPV integration begins with DNA damage or double strand break induced either by oxidative stress or HPV proteins and the subsequent steps are driven by the DNA damage responses. Inflammation and oxidative stress could be considered as cofactors in stimulating viral integration and deregulation of cellular and viral oncogenes during the progression of cervical carcinoma. All these events together with the host and viral genetic and epigenetic modifications in neoplastic progression have also been reviewed which may be relevant in identifying a new preventive therapeutic strategy. In the absence of therapeutic intervention for HPV-infected individuals, future research focus should be directed towards preventing and reversing of HPV integration. DNA damage response, knocking out integrated HPV sequences, siRNA approach, modulating the selection mechanism of cells harboring integrated genomes and epigenetic modifiers are the possible therapeutic targets.

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Section: Entry Of Hpv and Life Cycle In Cervical Epithelial Cellmentioning

confidence: 99%

Molecular mechanisms of HPV mediated neoplastic progression

Senapati¹,

Senapati²,

Dwibedi³

2016

Infect Agents Cancer

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“…The importance of the DNA damage response (DDR) to HPV replication is becoming increasingly clear (McKinney et al, 2015). Previous studies identified a role for the DDR kinase ATM (Ataxia Telangiectasia-Mutated) in productive replication of HPV31 (Moody and Laimins, 2009), which may facilitate viral DNA synthesis, at least in part, through the recruitment of DNA repair factors to viral replication centers (Chappell et al, 2015; Gillespie et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

HPV31 utilizes the ATR-Chk1 pathway to maintain elevated RRM2 levels and a replication-competent environment in differentiating Keratinocytes

et al. 2016

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Productive replication of human papillomaviruses (HPV) is restricted to the uppermost layers of the differentiating epithelia. How HPV ensures an adequate supply of cellular substrates for viral DNA synthesis in a differentiating environment is unclear. Here, we demonstrate that HPV31 positive cells exhibit increased dNTP pools and levels of RRM2, a component of the ribonucleotide reductase (RNR) complex, which is required for de novo synthesis of dNTPs. RRM2 depletion blocks productive replication, suggesting RRM2 provides dNTPs for viral DNA synthesis in differentiating cells. We demonstrate that HPV31 regulates RRM2 levels through expression of E7 and activation of the ATR-Chk1-E2F1 DNA damage response, which is essential to combat replication stress upon entry into S-phase, as well as for productive replication. Our findings suggest a novel way in which viral DNA synthesis is regulated through activation of ATR and Chk1 and highlight an intriguing new virus/host interaction utilized for viral replication.

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“…In response to DNA damage, Chk1 is rapidly activated, transduces the checkpoint signal, and finally facilitates cell cycle arrest and DDR [37,38]. Recent studies have shown that HPVs utilized DDR machinery to facilitate productive viral replication [11,39,40]. The level of phosphorylated Chk1 was enhanced and sustained in HPV16 E6-expressing fibroblasts [41].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that the importance of the cellular DNA damage response (DDR) to the viral replication is becoming increasing clear [11][12][13]. The act of DDR requires the activation of 4 protein kinases that form canonical ATM-Chk2 and ATR-Chk1 pathway [14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Checkpoint Kinase 1 Is Overexpressed during HPV16-Induced Cervical Carcinogenesis

Wei¹,

Chen²

2018

Gynecol Obstet Invest

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Purpose: Cervical cancer is one of the leading causes of cancer death among women worldwide. Checkpoint kinase 1 (Chk1) has a critical role in DNA damage response and cell cycle checkpoint control. Emerging evidence suggests that Chk1 promotes tumor growth. However, whether Chk1 is important for development of cervical cancer is largely unknown. Methods: The levels of Chk1 mRNA expression were determined using quantitative real-time polymerase chain reaction in a panel of 90 cervical specimens, including 30 cervical cancer tissues, 30 CIN II–III, and 30 normal cervical tissues. We investigated the correlation between Chk1 and HPV16 E6/E7 at the mRNA level using another 30 CIN II–III and 32 cervical cancer tissues with HPV16 infection. MTT and cell cycle assays were conducted to show the function role of Chk1 in cervical cancer SiHa cells. Results: Chk1 was gradually increased during cervical lesion progression and positively correlated with HPV16 E6/E7 expression. Inhibition of Chk1 resulted in suppressed cell proliferation concomitant with the blocking of cell cycle at S-phase in cervical cancer SiHa cells. Conclusions: These results indicate that maintained Chk1 expression by HPV16 E6/E7 in cervical cancer cells promotes cell growth by blocking the cell cycle progression, and may point to novel strategies for targeting Chk1 in cancer therapy.

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The Role of the DNA Damage Response throughout the Papillomavirus Life Cycle

Cited by 69 publications

References 120 publications

Molecular mechanisms of HPV mediated neoplastic progression

Molecular mechanisms of HPV mediated neoplastic progression

HPV31 utilizes the ATR-Chk1 pathway to maintain elevated RRM2 levels and a replication-competent environment in differentiating Keratinocytes

Checkpoint Kinase 1 Is Overexpressed during HPV16-Induced Cervical Carcinogenesis

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