Jiaping Wu

Publications (2)15.08 Total impact

• Article: Simian virus 40 large T antigen disrupts genome integrity and activates a DNA damage response via Bub1 binding.

  Jennifer Hein, Sergei Boichuk, Jiaping Wu, Yuan Cheng, Raimundo Freire, Parmjit S Jat, Thomas M Roberts, Ole V Gjoerup
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  ABSTRACT: Simian virus 40 (SV40) large T antigen (LT) is a multifunctional protein that is important for viral replication and oncogenic transformation. Previously, infection of monkey or human cells with SV40 was shown to lead to the induction of DNA damage response signaling, which is required for efficient viral replication. However, it was not clear if LT is sufficient to induce the damage response and, if so, what the genetic requirements and functional consequences might be. Here, we show that the expression of LT alone, without a replication origin, can induce key DNA damage response markers including the accumulation of gamma-H2AX and 53BP1 in nuclear foci. Other DNA damage-signaling components downstream of ATM/ATR kinases were induced, including chk1 and chk2. LT also bound the Claspin mediator protein, which normally facilitates the ATR activation of chk1 and monitors cellular replication origins. Stimulation of the damage response by LT depends mainly on binding to Bub1 rather than to the retinoblastoma protein. LT has long been known to stabilize p53 despite functionally inactivating it. We show that the activation of a DNA damage response by LT via Bub1 appears to play a major role in p53 stabilization by promoting the phosphorylation of p53 at Ser15. Accompanying the DNA damage response, LT induces tetraploidy, which is also dependent on Bub1 binding. Taken together, our data suggest that LT, via Bub1 binding, breaches genome integrity mechanisms, leading to DNA damage responses, p53 stabilization, and tetraploidy.
  Journal of Virology 11/2008; 83(1):117-27. · 5.40 Impact Factor
• Source

  Available from: pnas.org

  Article: Surveillance mechanism linking Bub1 loss to the p53 pathway.

  Ole V Gjoerup, Jiaping Wu, Devin Chandler-Militello, Grace L Williams, Jean Zhao, Brian Schaffhausen, Parmjit S Jat, Thomas M Roberts
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  ABSTRACT: Bub1 is a kinase believed to function primarily in the mitotic spindle checkpoint. Mutation or aberrant Bub1 expression is associated with chromosomal instability, aneuploidy, and human cancer. We now find that targeting Bub1 by RNAi or simian virus 40 (SV40) large T antigen in normal human diploid fibroblasts results in premature senescence. Interestingly, cells undergoing replicative senescence were also low in Bub1 expression, although ectopic Bub1 expression in presenescent cells was insufficient to extend lifespan. Premature senescence caused by lower Bub1 levels depends on p53. Senescence induction was blocked by dominant negative p53 expression or depletion of p21(CIP1), a p53 target. Importantly, cells with lower Bub1 levels and inactivated p53 became highly aneuploid. Taken together, our data highlight a role for p53 in monitoring Bub1 function, which may be part of a more general spindle checkpoint surveillance mechanism. Our data support the hypothesis that Bub1 compromise triggers p53-dependent senescence, which limits the production of aneuploid and potentially cancerous cells.
  Proceedings of the National Academy of Sciences 06/2007; 104(20):8334-9. · 9.68 Impact Factor