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This lab co-discovered the first human tumor suppressor gene, Retinoblastoma gene (RB), in late 1980 that plays essential roles in maintaining genomic stability and preventing tumor formation. Re-introduction of the wild-type Rb or p53 mediated by viral vectors suppresses tumor formation in animal studies. In addition, we have elucidated RB interaction networks, which modulate RB suppressing activity. One of the RB-interacting proteins, Hec1, is overly expressed in most cancer cells and plays essential roles in chromosome segregation by interacting with several proteins that modulate the G2/M phase. Inactivation of Hec1 led to cell death due to abnormal chromosomal segregation. Importantly, Hec1 is phosphorylated by a mitotic kinase, Nek2, which is essential for Hec1 function in chromosome segregation. We have identified small molecules that disrupt the interaction between Nek2 and Hec1, and may offer a novel agent to treat cancer.
In addition, we worked on two human breast cancer susceptibility genes, BRCA1 & BRCA2 and have established their dual participation in transcription regulation and DNA damage repair. BRCA1 has been shown to associate directly with the RAD50/MRE11/NBS1 complex, which functions in both non-homologous end-joining and homologous recombination repair of DNA double-strand breaks. The BRCA2 via its BRC repeats binds to RAD51, which catalyzes homologous DNA pairing and DNA strand exchange in an in vitro recombination reaction. Expression of a wild-type BRC repeat disrupted this interaction and rendered cells hypersensitive to gamma-irradiation and failed to activate the G2/M checkpoint. Small molecules that disrupt the interaction between BRC repeat and Rad51 have been isolated. These small compounds offer a potential to develop new combinatorial treatment with chemotherapy or radiation therapy.
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