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Topic Overview:
Maintaining a cell’s genomic integrity is critical because DNA alterations or disruptions can lead to various disease states, including cancer.  DNA damage can result from a number of cellular insults, including external factors, like chemical exposure, ultraviolet light exposure, and ionizing radiation, and internal factors, like cellular metabolism and replication errors. Segregation errors during mitosis cause genetic alterations that may result in cell death or genomic vulnerability leading to cancer.  While various cellular mechanisms ensure precise DNA replication, when mistakes do occur, DNA damage response signaling is triggered. 

The simian virus 40 (SV40) large T antigen (LT) is a multi-functional protein important in viral replication and oncogenic transformation.  SV40 infection induces DNA damage response signaling, which is required for efficient viral replication. For a time, it was not clear whether SV40 LT alone was sufficient to induce the DNA damage response and, if so, what genetic requirements and functional consequences might be expected. 

Dr. Gjoerup determined that SV40 LT can destabilize the host cell’s genome and induce the DNA damage response.  He then explored the mechanisms underlying this process and found that the mitotic regulator Bub1, which is critical for preserving genomic integrity, interacts with SV40 LT.  More specifically, he noted that SV40 LT binding to Bub1 led to attenuation of the spindle checkpoint and could also induce polyploidy (extra sets of chromosomes).  DNA damage signaling components downstream of ATM/ATR (ATM and Rad3-related) kinases were activated, including the chk kinases.  SV40 LT is also known to stabilize p53, a protein mutated or lost in more than 50 percent of cancers, despite functionally inactivating it.  It now appears that p53 stabilization is another result of SV40 LT binding to Bub1 and the initiation of a DNA damage response.

Mutant analysis has demonstrated that SV40 LT binding to Bub1 is required for both oncogenic transformation and viral DNA replication.  By discerning the mechanisms underlying this process, Dr. Gjoerup’s results could provide a foundation for the development of a strategy for harnessing the DNA damage response and replication pathway for research or therapeutic intervention.