HTLV-1 Tax Oncoprotein Subverts the Cellular DNA Damage Response via Binding to DNA-dependent Protein Kinase

Durkin, Sarah S.; Guo, Xin; Fryrear, Kimberly A.; Mihaylova, Valia T.; Gupta, Saurabh; Belgnaoui, S. Mehdi; Haoudi, Abdelali; Kupfer, Gary M.; Semmes, O. John

doi:10.1074/jbc.m804931200

Cited by 77 publications

(82 citation statements)

References 77 publications

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“…However, the Tax-DNA-PK complex was incapable of repairing new DNA DSBs induced by genotoxic stimuli in ATL cells. 48,49 Considering these results, impairment of DNA-PK mediated DNA DSB repair could be associated with genetic instability and cell transformation in the Tax-dependent early stage of ATL, whereas overexpression of DNA-PK or elevated DNA-PK activity could be associated with multidrugresistant phenotypes in overt ATL, as reported in other types of cancers. [42][43][44][45][46][47] In our experiments, it was difficult to analyze the association of Tax expression and effect of NK314 or DNA-PK inhibitor on cell growth inhibition in ATL cells because only one cell line (MT-2) expressed a detectable amount of Tax protein (data not shown).…”

Section: Discussionmentioning

confidence: 79%

NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase

Hisatomi

Sueoka‐Aragane

Sato

et al. 2011

Blood

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Section: Discussionmentioning

confidence: 79%

NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase

Hisatomi

Sueoka‐Aragane

Sato

et al. 2011

Blood

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“…Recent studies also suggest that DNA damage and H2AX phosphorylation in Tax-expressing cells result from induction of reactive oxygen species 9 and/or sequestration of DDR-associated proteins in TSS. [41][42][43] It thus appears that several Tax activities contribute to DSB formation and DDR pathway engagement. Finally, whereas DDR activation would be detrimental for viral persistence, our data (M.B.…”

Section: Discussionmentioning

confidence: 99%

Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program

Boxus

Twizere

Legros

et al. 2012

Blood

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The Tax oncoprotein encoded by the human T-cell leukemia virus type 1 plays a pivotal role in viral persistence and pathogenesis. Human T-cell leukemia virus type 1-infected cells proliferate faster than normal lymphocytes, expand through mitotic division, and accumulate genomic lesions. Here, we show that Tax associates with the minichromosome maintenance MCM2-7 helicase complex and localizes to origins of replication. Tax IntroductionHuman T-cell leukemia virus-1 (HTLV-1) is a retrovirus that infects approximately 20 million people worldwide. 1 Although the majority of infected people remain lifelong asymptomatic carriers, 2% to 5% develop either adult T-cell leukemia (ATL) or chronic inflammatory diseases, such as HTLV-1-associated myelopathy/tropical spastic paraparesis. 1 Two major hallmarks of HTLV-1-infected cells are: preferential proliferation compared with normal lymphocytes 2 and tendency to accumulate genomic lesions, a prerequisite for oncogenesis. 3,4 Although the molecular mechanisms underlying T-cell transformation remain to be elucidated, it is generally accepted that the virally encoded Tax protein plays a central role. Tax indeed displays pleiotropic activities that cooperate to drive cell cycle progression and perturb genome stability. 4,5 For example, Tax shortens G 1 phase and accelerates transition into S phase by manipulating positive and negative G 1 phase regulators (ie, cyclin D/CDK complex, Rb and CDK inhibitors). [6][7][8] In addition, Tax is thought to indirectly generate DNA damage by suppressing DNA repair processes and competing with cellular DNA damage response (DDR). 4,5 Recent data also support a direct role for Tax-induced reactive oxygen species in the occurrence of DNA lesions. 9 Conceptually, Tax activities are achieved through proteinprotein interactions in both nuclear and cytoplasmic cellular compartments. 10 In the nucleus, Tax accumulates within foci called Tax speckled structures (TSS), 11 which overlap with the cellular machinery required for transcription, splicing, post-transcriptional modifications of proteins, DNA repair, and checkpoint control. 12 In this report, we further demonstrate that Tax recruits the MCM2-7 replicative helicase within the TSS and modulates the program of replication origin firing. Notably, this mechanism favors cell cycle progression and directly compromises genome stability. Methods Plasmids, antibodies, yeast 2-hybrid, and GST pulldownSee supplemental Methods (available on the Blood Web site; see the Supplemental Materials link at the top of the online article). Cell cultureHeLa, Rat-1, and 293GP2 cells were cultured in Dulbecco modified Eagle medium supplemented with 10% FBS and 2mM l-glutamine and penicillin/ streptomycin. Jurkat, HUT78 and JPX9 (Jurkat cell lines stably transfected either with tax-1 gene driven by a metallothionein-inducible promoter) were kept in RPMI 1640 supplemented with 10% FBS, 2mM l-glutamine, and penicillin/streptomycin. Expression of the viral protein was induced in JPX9 cells by adding 120 M zinc chloride...

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“…Although only a small percentage of ATL patients have genomic p53 mutations, the TAX protein interferes with the DDR pathway through inactivation of p53 (for a review see (Tabakin-Fix et al, 2006)). TAX also restricts activity of ATM, DNA -PK, CHK1 and CHK2-mediated checkpoints at G1 or G2/M (Marriott and Semmes, 2005;Chandhasin et al, 2008;Durkin et al, 2008). As a result, TAX limits cell cycle arrest induced by exogenous DNAdamaging agents.…”

Section: Role Of Genomic Instabilities In Transformationmentioning

confidence: 99%

Mechanisms of HTLV-1 persistence and transformation

2009

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HTLV-1 Tax Oncoprotein Subverts the Cellular DNA Damage Response via Binding to DNA-dependent Protein Kinase

Cited by 77 publications

References 77 publications

NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase

NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase

Interaction of HTLV-1 Tax with minichromosome maintenance proteins accelerates the replication timing program

Mechanisms of HTLV-1 persistence and transformation

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