Welcome to the Wu Lab Home Page
Xiaohua Wu, Ph.D.
Tel: 858-784-7910
Fax:858-784-7978
e-mail: xiaohwu@scripps.edu

Currently, a postdoctoral training position is available for a highly motivated and enthusiastic fellow to join our team!
Research Interest
Genome instability is a hallmark of the malignant phenotype and a driving force for tumorigenesis. Cell cycle checkpoints have evolved to monitor the integrity of the eukaryotic genome and ensure the completion of DNA replication and the repair of damaged DNA before cell cycle progression. However, it is still not well defined how checkpoints are activated and coordinated with DNA damage repair at the molecular level. We are interested in determining the mechanisms underlying cell cycle checkpoint control in order to address how cell cycle arrest is coordinated with DNA damage repair to maintain genome stability and prevent cancer.

One of our research focuses is on the Mre11/Rad50/Nbs1 complex (MRN), which participates in multiple pathways to maintain genome stability. In humans, hypomorphic mutations in NBS1 and MRE11 lead to Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia-like disorder (ATLD), respectively. NBS and ATLD patients are highly prone to cancer and cells from these patients are sensitive to radiation, exhibit chromosomal instability and show defects in the S-phase checkpoint. Recent studies demonstrate that MRN is required for checkpoint activation while serving as a substrate of the checkpoint kinases ATM and ATR upon DNA damage. This complex interacts with multiple checkpoint proteins including Brca1, RPA and MDC1. Currently, we are engaged in the following projects to study the function of the MRN complex. (1). We are characterizing damage-induced phosphorylation modification of MRN and probe the relevant biological functions in checkpoint control and damage repair. (2). We are establishing repair assay systems to study the function of MRN in DNA DSB repair. (3). We are using biochemical purification approaches to isolate Nbs1 complexes to establish functional links between Nbs1 and other important regulators in the checkpoint network. (4). We are studying the role of MRN in the S-phase associated damage responses.

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. Re-replication 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 re-replication, so that disruption of licensing control by the overexpression of the licensing factor, Cdt1, fails to induce significant re-replication in mammalian cells when the ATR checkpoint is intact. Currently, we are focusing on the following questions. (1). How is Cdt1 stability regulated during the cell cycle and in response to DNA damage? (2). How does the cell cycle checkpoint sense the loss of replication licensing control? (3). How does the activated checkpoint suppress re-replication and re-replication-associated DNA damage? (4). How does loss of replication control contribute to tumorigenesis?
 
Representative Publications
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, In press. (*equal contribution)

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. (*equal contribution)

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., In press.

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. (*equal contribution)

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., Livingston, D.M. (2004) SV40 T antigen interacts with Nbs1 to disrupt DNA replication control. Genes Dev. 18:1305-1316.

Liu, E., Li, X., Yan, F., Zhao Q., 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’Neill, 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 MATα donor preference during mating-type switching of Saccharomyces cerevisiae. Mol Cell Biol. 16: 657-668.

Wu, X. and Haber, J.E. (1995).MATα donor preference in yeast mating-type switching: activation of a large chromosomal region for recombination. Genes Dev. 9:1922-1932.
 
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