p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

Wiebusch, Lüder; Hagemeier, Christian

doi:10.1038/onc.2010.99

Cited by 69 publications

(112 citation statements)

References 58 publications

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“…APC is a multicomponent ubiquitin ligase well known to regulate the cell cycle. Several recent studies have indicated that APC is activated upon DNA damage in an ATM-dependent as well as an ATMindependent manner (55)(56)(57). Although it is not clear whether NF-B was involved in the DDR-induced APC activation in these studies, it is reasonable to speculate that E1-dependent activation of DDR induces activation of APC, possibly through NF-B.…”

Section: Activation Of Nf-b By E1 Through Ddrmentioning

confidence: 85%

Activation of NF-κB by Human Papillomavirus 16 E1 Limits E1-Dependent Viral Replication through Degradation of E1

Nakahara

Tanaka

Ohno

et al. 2015

J Virol

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NF-B is a family of transcription factors that regulate gene expression involved in many processes, such as the inflammatory response and cancer progression. Little is known about associations of NF-B with the human papillomavirus (HPV) life cycle. We have developed a tissue culture system to conditionally induce E1-dependent replication of the human papillomavirus 16 (HPV16) genome in human cervical keratinocytes and found that expression of HPV16 E1, a viral helicase, results in reduction of IB␣ and subsequent activation of NF-B in a manner dependent on helicase activity. Exogenous expression of a degradation-resistant mutant of IB␣, which inhibits the activation of NF-B, enhanced E1-dependent replication of the viral genome. Wortmannin, a broad inhibitor of phosphoinositide 3-kinases (PI3Ks), and, to a lesser extent, VE-822, an ATR kinase inhibitor, but not KU55933, an ATM kinase inhibitor, suppressed the activation of NF-B and augmented E1-dependent replication of the HPV16 genome. Interestingly, the enhancement of E1-dependent replication of the viral genome was associated with increased stability of E1 in the presence of wortmannin as well as the IB␣ mutant. Collectively, we propose that expression of E1 induces NF-B activation at least in part through the ATR-dependent DNA damage response and that NF-B in turn limits E1-dependent replication of HPV16 through degradation of E1, so that E1 and NF-B may constitute a negative feedback loop. IMPORTANCE A major risk factor in human papillomavirus (HPV)-associated cancers is persistent infection with high-risk HPVs. To eradicate viruses from infected tissue, it is important to understand molecular mechanisms underlying the establishment and maintenance of persistent infection. In this study, we obtained evidence that human papillomavirus 16 (HPV16) E1, a viral DNA helicase essential for amplification of the viral genomes, induces NF-B activation and that this limits E1-dependent genome replication of HPV16. These results suggest that NF-B mediates a negative feedback loop to regulate HPV replication and that this feedback loop could be associated with control of the viral copy numbers. We could thus show for the first time that NF-B activity is involved in the establishment and maintenance of persistent HPV infection. Human papillomaviruses (HPVs) are a large family of nonenveloped, small DNA viruses with an approximately 8-kbp double-stranded circular genome that infect stratified squamous epithelium in various anatomical sites such as skin, the anogenital tract, and the oral cavity. Virus infection can cause hyperproliferative lesions, ranging from verrucae to cancer. To date, at least 180 types of HPVs have been cloned from clinical lesions and classified as either cutaneous or mucosal types based on their predilection for different sites of infection. A subset of mucosal HPVs, high-risk HPVs (HR-HPVs), such as HPV16, are strongly associated with anogenital cancers, including nearly 100% of cervical cancers and some proportion of head and neck cancers...

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Section: Activation Of Nf-b By E1 Through Ddrmentioning

confidence: 85%

Activation of NF-κB by Human Papillomavirus 16 E1 Limits E1-Dependent Viral Replication through Degradation of E1

Nakahara

Tanaka

Ohno

et al. 2015

J Virol

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“…This initiates the destruction of cyclin B1 and a decrease in Cdk activity, which is required to allow Cdh1-dependent activation of the APC/C during the late stages of mitosis and throughout G1. DNA damage in G2 can activate APC/C Cdh1 , which is essential for a persistent G2 arrest and requires p53-and p21-dependent Cdk inhibition (Bassermann et al, 2008;Lee et al, 2009;Sudo et al, 2001;Wiebusch and Hagemeier, 2010). Premature activation of the APC/C Cdh1 in G2 by DNA damage targets many proteins required for mitotic entry for destruction, including cyclin A, cyclin B1 and Plk1, thus preventing recovery from a G2 arrest (Fig.…”

Section: Degradation Of Cell Cycle Proteins Regulates Recovery Competmentioning

confidence: 99%

“…Premature activation of the APC/C Cdh1 in G2 by DNA damage targets many proteins required for mitotic entry for destruction, including cyclin A, cyclin B1 and Plk1, thus preventing recovery from a G2 arrest (Fig. 4A) (Johmura et al, 2014;Krenning et al, 2014;Lee et al, 2009;Lindqvist et al, 2009b;Wiebusch and Hagemeier, 2010). The resulting cells that have a G2 DNA content but lack G2-specific protein expression are committed to senescence (Johmura et al, 2014;Ye et al, 2013).…”

Section: Degradation Of Cell Cycle Proteins Regulates Recovery Competmentioning

confidence: 99%

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

Shaltiël

Krenning

Bruinsma

et al. 2015

Journal of Cell Science

254

272

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Cell cycle checkpoints activated by DNA double-strand breaks (DSBs) are essential for the maintenance of the genomic integrity of proliferating cells. Following DNA damage, cells must detect the break and either transiently block cell cycle progression, to allow time for repair, or exit the cell cycle. Reversal of a DNA-damageinduced checkpoint not only requires the repair of these lesions, but a cell must also prevent permanent exit from the cell cycle and actively terminate checkpoint signalling to allow cell cycle progression to resume. It is becoming increasingly clear that despite the shared mechanisms of DNA damage detection throughout the cell cycle, the checkpoint and its reversal are precisely tuned to each cell cycle phase. Furthermore, recent findings challenge the dogmatic view that complete repair is a precondition for cell cycle resumption. In this Commentary, we highlight cell-cycle-dependent differences in checkpoint signalling and recovery after a DNA DSB, and summarise the molecular mechanisms that underlie the reversal of DNA damage checkpoints, before discussing when and how cell fate decisions after a DSB are made.

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“…2). However, subsequent work in several laboratories provided evidence that this is also due to protein degradation triggered by anaphase-promoting complex/cyclosome (APC/C) and its co-activator Cdh1 [74][75][76] (Fig. 2).…”

Section: Senescence In G2 -An Old Concept Awaiting Wider Recognitionmentioning

confidence: 99%

“…93 Moreover, stable G2 arrest induced by ionizing radiation (IR) was associated with p53/p21-dependent premature APC/C Cdh1 activation and degradation of mitotic cyclins, consistent with previous observations. [74][75][76] However, unlike p53-mediated mitotic bypass, APC/C Cdh1 activation alone does not appear to be sufficient to induce senescence, that additionally requires repression of mitotic regulators by pRb family pocket proteins (Fig. 2).…”

Section: Senescence In G2 -An Old Concept Awaiting Wider Recognitionmentioning

confidence: 99%

Senescence from G2 arrest, revisited

2015

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p53- and p21-dependent premature APC/C–Cdh1 activation in G2 is part of the long-term response to genotoxic stress

Cited by 69 publications

References 58 publications

Activation of NF-κB by Human Papillomavirus 16 E1 Limits E1-Dependent Viral Replication through Degradation of E1

Activation of NF-κB by Human Papillomavirus 16 E1 Limits E1-Dependent Viral Replication through Degradation of E1

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

Senescence from G2 arrest, revisited

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