Human T-cell leukemia virus-I tax oncoprotein functionally targets a subnuclear complex involved in cellular DNA damage-response

J Biol Chem. 2003 Sep 26;278(39):37736-44. doi: 10.1074/jbc.M301649200. Epub 2003 Jul 2.

Abstract

The virally encoded oncoprotein Tax has been implicated in HTLV-1-mediated cellular transformation. The exact mechanism by which this protein contributes to the oncogenic process is not known. However, it has been hypothesized that Tax induces genomic instability via repression of cellular DNA repair. We examined the effect of de novo Tax expression upon the cell cycle, because appropriate activation of cell cycle checkpoints is essential to a robust damage-repair response. Upon induction of tax expression, Jurkat T-cells displayed a pronounced accumulation in G2/M that was reversible by caffeine. We examined the G2-specific checkpoint signaling response in these cells and found activation of the ATM/chk2-mediated pathway, whereas the ATR/chk1-mediated response was unaffected. Immunoprecipitation with anti-chk2 antibody results in co-precipitation of Tax demonstrating a direct interaction of Tax with a chk2-containing complex. We also show that Tax targets a discrete nuclear site and co-localizes with chk2 and not chk1. This nuclear site, previously identified as Tax Speckled Structures (TSS), also contains the early damage response factor 53BP1. The recruitment of 53BP1 to TSS is dependent upon ATM signaling and requires expression of Tax. Specifically, Tax expression induces redistribution of diffuse nuclear 53BP1 to the TSS foci. Taken together these data suggest that the TSS describe a unique nuclear site involved in DNA damage recognition, repair response, and cell cycle checkpoint activation. We suggest that association of Tax with this multifunctional subnuclear site results in disruption of a subset of the site-specific activities and contributes to cellular genomic instability.

MeSH terms

  • Carrier Proteins / metabolism
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2
  • DNA Damage*
  • Enzyme Activation
  • G2 Phase
  • Gene Products, tax / physiology*
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Jurkat Cells
  • Phosphoproteins*
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases*
  • RNA, Small Interfering / metabolism
  • Tumor Suppressor p53-Binding Protein 1

Substances

  • Carrier Proteins
  • Gene Products, tax
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • RNA, Small Interfering
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Protein Kinases
  • Checkpoint Kinase 2
  • CHEK1 protein, human
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • Protein-Serine-Threonine Kinases