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Xiaohua Wu, Ph.D.
Tel: 858-784-7910
Fax:858-784-7978
e-mail: xiaohwu@scripps.edu



Research Interest


        We are interested in the molecular mechanisms underlying the maintenance of genome stability in mammalian cells. Defects in these mechanisms are highly associated with cancer and aging. Various approaches such as biochemical, cell-based and animal model-based studies are utilized to understand the molecular basis of genome stability control and its relevance to cancer and aging in our laboratory.

        DNA repair mechanisms are critical for the maintenance of genome stability. Cell cycle checkpoints have evolved to monitor the integrity of the eukaryotic genome and to ensure the completion of DNA repair before cell cycle progression. One of our research focuses is to understand the mechanisms of the checkpoint control and DNA repair in the maintenance of genome stability. We are particularly interested in the role of a number of disease-linked proteins, including the breast cancer suppressor BRCA1, and genome-instability-associated genes, Nbs1, Mre11 and ATM in the DNA damage response network. We are engaged in the following directions to elucidate the mechanisms of the maintenance of genome stability. First, we study how DNA damage signals are transduced to activate the checkpoints and regulate DNA damage repair by analyzing post-translational modifications, such as phosphorylation, ubiquitination and sumoylation. Second, we study the mechanisms underlying DNA double-stranded break repair. We have established various GFP-based repair assays to monitor the repair process in order to elucidate the exact mechanisms at the molecular level. Third, we study the role of checkpoint and repair mechanisms in the protection of replication forks under replication stress condition and in the promotion of replication restart. Fourth, we use biochemical approaches to study the enzymatic activities of the proteins in the DNA damage response network, which provides biochemical basis for the cellular and biological functions of the critical players in the maintenance of genome stability.

        The second focus of our research is to understand how DNA replication is controlled so that DNA is replicated once and only once per cell cycle. Rereplication of the genome, or even a segment of it, could lead to genome instability. Recently, we showed that the ATR-mediated S-phase checkpoint acts as a surveillance mechanism to prevent rereplication when the replication licensing control is impaired. Currently, we are focusing on the following questions. (1). How does the cell cycle checkpoint sense the loss of replication licensing control and suppress DNA rereplication? (2). How is DNA damage associated rereplication repaired to maintain genome stability? (3). How does loss of replication control contribute to tumorigenesis?

        The third focus is to understand how chromosomal translocation is suppressed to prevent cancer development. Chromosome translocation arises when a broken chromosome mistakenly rejoins with another chromosome, which may activate oncogenes and lead to tumorigenesis. A large array of recurrent and non-random chromosomal translocations is associated with hematological cancers, and most of these translocations are causal events for malignant transformation. For instance, translocations are frequently observed in both de novo and therapy-related acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). We are developing cancer-relevant translocation assays and mouse models for analyzing chromosomal translocations in vivo. Identifying the molecular mechanism of how translocations develop is of great importance to the understanding of the etiology of hematological cancers and other types of cancers. It will also help to develop therapeutic interventions to prevent de novo and therapy-related recurring hematological cancers that are associated with translocations.

        Furthermore, we investigate the mechanisms of DNA repair in cancer stem cells and search for therapeutic targets that can be used to eradicate cancer stem cells, providing valuable information for developing therapeutic interventions for cancer. We are also developing mouse models to study DNA repair activities in stem cells and in somatic cells during the process of aging.
 

Representative Publications


Chen, L., Nievera, C., Lee A. and Wu, X. (2008) Cell cycle-dependent complex formation of BRCA1/CtIP/Mre11-Rad50-Nbs1 is important for DNA double-strand break repair. J Biol Chem. 283: 7713-7720.

Liu E., Lee A.Y., Chiba T., Olson E. Sun P. and Wu X. (2007) ATR-mediated S-phase checkpoint prevents DNA rereplication in mammalian cells when the licensing control is disrupted. Journal of Cell Biology 179: 643-657.

Olson E., Nievera C.J., Liu E., Lee A.Y., Chen L. and Wu X. (2007) The Mre11 complex mediates the S-phase checkpoint through an interaction with RPA. Molecular and Cellular Biology, 27: 6053-6067.

Lee A.Y., Liu E. and Wu X. (2007) The Mre11/Rad50/Nbs1 complex plays an important role in the prevention of DNA rereplication in mammalian cells. J Biol Chem. 282: 32243-32255.

Olson E., Nievera C.J., Lee A.Y., Chen L. and Wu X. (2007) The Mre11 complex acts both upstream and downstream of ATR to regulate the S-phase checkpoint following UV treatment J Biol Chem. 282: 22939-22952.

Olson E., Nievera C. J., Klimovich V., Fanning E. and Wu X. (2006) RPA2 is a direct downstream target for ATR to regulate the S-phase checkpoint. J Biol Chem. 281: 39517-39533.

Wu, X.*, Avni, D., Chiba, T., Yan, F., Zhao, Q., Lin, Y., Heng, H.H.Q. and Livingston, D.M.* (2004) SV40 T antigen interacts with Nbs1 to disrupt DNA replication control. Genes & Development 18:1305-1316. *Corresponding authors.

Liu, E., Li, X., Yan, F., Zhao Q. and Wu, X. (2004) Cyclin-dependent kinases phosphorylate human Cdt1 and induce its degradation. J Biol Chem. 279: 17283-17288.

Li, X., Zhao, Q., Liao, R., Sun, P. and Wu, X. (2003) The SCFSkp2 ubiquitin ligase complex interacts with the human replication licensing factor Cdt1 and regulates Cdt1 degradation. J Biol Chem. 278: 30854-30858.

Wu, X., Rathbun, G., Lane, W.S., Weaver, D.T. and Livingston, D.M. (2000) Communication of the Nijmegen Breakage Syndrome Protein with ATM and BRCA1. Cold Spring Harbor Symposia on Quantitative Biology LXV: 535-545.

Wu, X., Ranganathan, V., Weisman, D.S., Heine, W.F., Ciccone, D.N., O\u2019Neill, T.B., Crick, K.E., Pierce, K.A., Lane, W.S., Rathbun, G., Livingston, D.M. and Weaver, D.T. (2000). ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature 405: 477-482.

Wu, X., Heine, W.F., Petrini, J.H.J., Weaver, D.T., Livingston, D.M. and Chen, J. (2000). Independence of Nbs1/Mre11/Rad50 nuclear focus formation and the presence of intact BRCA1. Science 289: 11 (website: www.sciencemag.org/cgi/content/full/289/5476/11a).

Wu, X., Wu, C. and Haber, J.E. (1997). Rules of donor preference in yeast mating-type gene switching revealed by a competition assay involving two types of recombination. Genetics 147: 399-407.

Wu, X., Haber, J.E. (1996) A 700 bp cis-acting region controls mating-type dependent recombination along the entire left arm of yeast chromosome III. Cell 87: 277-285.

Wu, X., Moore, J.K. and Haber, J.E. (1996). Mechanism of MATa donor preference during mating-type switching of Saccharomyces cerevisiae. Mol. Cell Biol. 16: 657-668. Wu, X. and Haber, J.E. (1995). MATa donor preference in yeast mating-type switching: activation of a large chromosomal region for recombination. Genes & Dev. 9:1922-1932.




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