Activation of WIP1 Phosphatase by HTLV-1 Tax Mitigates the Cellular Response to DNA Damage

Dayaram, Tajhal; Lemoine, Francene J.; Donehower, Lawrence A.; Marriott, Susan J.
February 2013
PLoS ONE;Feb2013, Vol. 8 Issue 2, p1
Academic Journal
Genomic instability stemming from dysregulation of cell cycle checkpoints and DNA damage response (DDR) is a common feature of many cancers. The cancer adult T cell leukemia (ATL) can occur in individuals infected with human T cell leukemia virus type 1 (HTLV-1), and ATL cells contain extensive chromosomal abnormalities, suggesting that they have defects in the recognition or repair of DNA damage. Since Tax is the transforming protein encoded by HTLV-1, we asked whether Tax can affect cell cycle checkpoints and the DDR. Using a combination of flow cytometry and DNA repair assays we showed that Tax-expressing cells exit G1 phase and initiate DNA replication prematurely following damage. Reduced phosphorylation of H2AX (γH2AX) and RPA2, phosphoproteins that are essential to properly initiate the DDR, was also observed in Tax-expressing cells. To determine the cause of decreased DDR protein phosphorylation in Tax-expressing cells, we examined the cellular phosphatase, WIP1, which is known to dephosphorylate γH2AX. We found that Tax can interact with Wip1 in vivo and in vitro, and that Tax-expressing cells display elevated levels of Wip1 mRNA. In vitro phosphatase assays showed that Tax can enhance Wip1 activity on a γH2AX peptide target by 2-fold. Thus, loss of γH2AX in vivo could be due, in part, to increased expression and activity of WIP1 in the presence of Tax. siRNA knockdown of WIP1 in Tax-expressing cells rescued γH2AX in response to damage, confirming the role of WIP1 in the DDR. These studies demonstrate that Tax can disengage the G1/S checkpoint by enhancing WIP1 activity, resulting in reduced DDR. Premature G1 exit of Tax-expressing cells in the presence of DNA lesions creates an environment that tolerates incorporation of random mutations into the host genome.


Related Articles

  • Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response. Marriott, Susan J.; Semmes, Oliver John // Oncogene;9/5/2005, Vol. 24 Issue 39, p5986 

    Human T-cell lymphotropic virus type I (HTLV-I) is the etiologic agent of adult T-cell leukemia (ATL), a rapidly progressing, clonal malignancy of CD4+ T lymphocytes. Fewer than one in 20 infected individuals typically develop ATL and the onset of this cancer occurs after decades of relatively...

  • Role of multifunctional transcription factor TFII-I and putative tumour suppressor DBC1 in cell cycle and DNA double strand damage repair. Tanikawa, M; Wada-Hiraike, O; Yoshizawa-Sugata, N; Shirane, A; Hirano, M; Hiraike, H; Miyamoto, Y; Sone, K; Ikeda, Y; Kashiyama, T; Oda, K; Kawana, K; Katakura, Y; Yano, T; Masai, H; Roy, A L; Osuga, Y; Fujii, T // British Journal of Cancer;12/10/2013, Vol. 109 Issue 12, p3042 

    Background:In multicellular organisms, precise control of cell cycle and the maintenance of genomic stability are crucial to prevent chromosomal alterations. The accurate function of the DNA damage pathway is maintained by DNA repair mechanisms including homologous recombination (HR). Herein, we...

  • Nbs1 is required for ATR-dependent phosphorylation events. Stiff, Tom; Reis, Caroline; Alderton, Gemma K.; Woodbine, Lisa; O'Driscoll, Mark; Jeggo, Penny A. // EMBO Journal;1/12/2005, Vol. 24 Issue 1, p199 

    Nijmegen breakage syndrome (NBS) is characterised by microcephaly, developmental delay, characteristic facial features, immunodeficiency and radiosensitivity. Nbs1, the protein defective in NBS, functions in ataxia telangiectasia mutated protein (ATM)-dependent signalling likely facilitating ATM...

  • Chromatin Relaxation-Mediated Induction of p19INK4d Increases the Ability of Cells to Repair Damaged DNA. Ogara, María F.; Sirkin, Pablo F.; Carcagno, Abel L.; Marazita, Mariela C.; Sonzogni, Silvina V.; Ceruti, Julieta M.; Cánepa, Eduardo T. // PLoS ONE;Apr2013, Vol. 8 Issue 4, p1 

    The maintenance of genomic integrity is of main importance to the survival and health of organisms which are continuously exposed to genotoxic stress. Cells respond to DNA damage by activating survival pathways consisting of cell cycle checkpoints and repair mechanisms. However, the signal that...

  • Response to DNA damage: why do we need to focus on protein phosphatases? Shimada, Midori; Nakanishi, Makoto // Frontiers in Oncology;Jan2013, Vol. 3, p1 

    Eukaryotic cells are continuously threatened by unavoidable errors during normal DNA replication or various sources of genotoxic stresses that cause DNA damage or stalled replication. To maintain genomic integrity, cells have developed a coordinated signaling network, known as the DNA damage...

  • Protein phosphatase 2A has an essential role in the activation of γ-irradiation-induced G2/M checkpoint response. Yan, Y.; Cao, P. T.; Greer, P. M.; Nagengast, E. S.; Kolb, R. H.; Mumby, M. C.; Cowan, K. H. // Oncogene;7/29/2010, Vol. 29 Issue 30, p4317 

    G2/M checkpoint activation after DNA damage results in G2/M cell cycle arrest that allows time for DNA repair before the entry of cells into mitosis. Activation of G2/M checkpoint involves a series of signaling events, which include activation of ataxia telangiectecia-mutated and Rad3-related...

  • Regulation of DNA double-strand break repair pathway choice. Shrivastav, Meena; De Haro, Leyma P.; Nickoloff, Jac A. // Cell Research;Jan2008, Vol. 18 Issue 1, p134 

    DNA double-strand breaks (DSBs) are critical lesions that can result in cell death or a wide variety of genetic alterations including large- or small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non-homologous end-joining (NHEJ) and...

  • Hyperactivation of DNA-PK by Double-Strand Break Mimicking Molecules Disorganizes DNA Damage Response. Quanz, Maria; Chassoux, Danielle; Berthault, Nathalie; Agrario, Céline; Jian-Sheng Sun; Dutreix, Marie // PLoS ONE;2009, Vol. 4 Issue 7, p1 

    Cellular response to DNA damage involves the coordinated activation of cell cycle checkpoints and DNA repair. The early steps of DNA damage recognition and signaling in mammalian cells are not yet fully understood. To investigate the regulation of the DNA damage response (DDR), we designed short...

  • Molecular and Biochemical Features in Alzheimer's Disease. Pall�s, Merc�; Camins, Antoni // Current Pharmaceutical Design;Nov2006, Vol. 12 Issue 33, p4389 

    The purpose of this review is to discuss the pathophysiological pathways involved in pathogenesis of Alzheimer's disease pointing out current and future pharmacological targets. Alzheimer's disease is one of the most important neurodegenerative disorders in the developed world together with...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics