The NBS1-ATM Connection Revisited

Difilippantonio, Simone; Nussenzweig, André

doi:10.4161/cc.6.19.4758

Cited by 49 publications

(45 citation statements)

References 64 publications

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“…8) strongly supports the notion that the MRN complex is required for replication of the MVC genome ( Fig. 10) and that its role may be to recruit DNA repair factors to the replication center (14,37), as p-Nbs1 is essential to DSB repair (29). On the other hand, the MRN complex senses ATM activation, which in turn may mediate proteasome-dependent degradation of the MRN subunit (94) at later stages of infection.…”

Section: Discussionsupporting

confidence: 61%

“…In addition, we found that in contrast to the results we obtained by silencing Mre11, knockdown of ATM reduced Nbs1 phosphorylation only slightly, indicating that a low level of activated ATM is sufficient to phosphorylate Nbs1. As Nbs1 is essential for DSB repair and genome stability (29), the persistent presence of p-Nbs1 in the MVC replication foci (Fig. 8A) suggests that this activated form may play a role in replication of the MVC genome.…”

Section: Vol 85 2011 Bocavirus Ddr Role In Dna Replication and Cellmentioning

confidence: 99%

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Bocavirus Infection Induces a DNA Damage Response That Facilitates Viral DNA Replication and Mediates Cell Death

Luo

Chen

Qiu

2011

J Virol

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no effect. Moreover, we identified that this ATM-mediated cell death is p53 dependent. In addition, we localized the Mre11-Rad50-Nbs1 (MRN) complex, the major mediator as well as a substrate of the ATM-mediated DNA damage response pathway to MVC replication centers during infection, and show that Mre11 knockdown led to a reduction in MVC DNA replication. Our findings are the first to support the notion that an autonomous parvovirus is able to hijack the host DNA damage machinery for its own replication and for the induction of cell death.

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Section: Discussionsupporting

confidence: 61%

Section: Vol 85 2011 Bocavirus Ddr Role In Dna Replication and Cellmentioning

confidence: 99%

Bocavirus Infection Induces a DNA Damage Response That Facilitates Viral DNA Replication and Mediates Cell Death

Luo

Chen

Qiu

2011

J Virol

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“…Eukaryotic cells have developed two alternative DSB repair methods, direct ligation of the excised DNA ends (nonhomologous end joining, NHEJ) and homologous recombination (HR) (12)(13)(14)(15). DNA repair is stimulated by a phosphorylation-based signaling cascade, the DNA damage response (DDR) (16)(17)(18).…”

mentioning

confidence: 99%

Nuclear phosphoinositide 3-kinase β controls double-strand break DNA repair

Kumar

Fernández-Capetillo

Carrera

2010

Proc. Natl. Acad. Sci. U.S.A.

150

140

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Class I phosphoinositide 3-kinases are enzymes that generate 3-poly-phosphoinositides at the cell membrane following transmembrane receptor stimulation. Expression of the phosphoinositide 3-kinase β (PI3Kβ) isoform, but not its activity, is essential for early embryonic development. Nonetheless, the specific function of PI3Kβ in the cell remains elusive. Double-strand breaks (DSB) are among the most deleterious lesions for genomic integrity; their repair is required for development. We show that PI3Kβ is necessary for DSB sensing, as PI3Kβ regulates binding of the Nbs1 sensor protein to damaged DNA. Indeed, Nbs1 did not bind to DSB in PI3Kβ-deficient cells, which showed a general defect in subsequent ATM and ATR activation, resulting in genomic instability. Inhibition of PI3Kβ also retarded the DNA repair but the defect was less marked than that induced by PI3Kβ deletion, supporting a kinase-independent function for PI3Kβ in DNA repair. These results point at class I PI3Kβ as a critical sensor of genomic integrity.

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“…Antibodies specific to phosphorylated ATM, pATM(S1981), and CHK2, pCHK2(T68), or CHK1, pCHK1(S345), were used as markers for ATM or ATR activation, respectively. NBS1 was also analyzed as it has been shown to be phosphorylated by ATM (5,44). Upon DOX incubation, phosphorylation of ATM and CHK1 was increased in the cell populations of tetON E1ϩE2 and tetON E1, although basal levels of the phosphorylated CHK1 appeared also higher in these cells (Fig.…”

Section: Hpv16 E1 Induces Activation Of Nf-b In Human Cervical Keratimentioning

confidence: 99%

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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The NBS1-ATM Connection Revisited

Cited by 49 publications

References 64 publications

Bocavirus Infection Induces a DNA Damage Response That Facilitates Viral DNA Replication and Mediates Cell Death

Bocavirus Infection Induces a DNA Damage Response That Facilitates Viral DNA Replication and Mediates Cell Death

Nuclear phosphoinositide 3-kinase β controls double-strand break DNA repair

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

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