Phang-Lang Chen
Ph.D., University of California, San Diego, 1991
University of California, Irvine
Irvine, CA 92697
(949) 824-4008
plchen@uci.edu
Research Interests:
My laboratory is interested in understanding the critical role of tumor suppressor genes in the genesis and progression of cancer. Currently, we are putting most of our efforts into elucidating the intracellular signaling pathways involved in the DNA damage response. We focus especially on molecules serving as transducers and effectors, including BRCA1 and BRCA2, members of the BRCT motif-containing family proteins such as NBS1, 53BP1 and NFBD1, and on the DNA repair machinery. Understanding these signal pathways is vital for solving the puzzle of how cells maintain their genome stability and how specific problems with DNA repair predispose to different cell type-specific cancers.
We have demonstrated that BRCA2 binds to the DNA double-strand break repair protein Rad51 through the BRC repeats, and have shown that the BRC repeats are necessary for normal resistance of cells to the effects of DNA-damaging agents. Additionally, experiments have shown that BRCA1 is associated with hRad50, the human counterpart of a yeast protein involved in DNA repair and recombination. Based on my work and that of others, it became apparent that BRCA1 and BRCA2 have separate but overlapping functions in maintaining genomic integrity, and their loss may predispose individuals to breast and other cancers such as ovarian and prostate.
Other ongoing studies focus on the product of the gene mutated in Nijmegen breakage syndrome (NBS). NBS cells are also deficient for radiation-induced nuclear foci containing the repair factor Mre11. An analysis of the kinetic relationship between Mre11 phosphorylation and the appearance of its radiation-induced foci indicates that the former precedes the latter. Together, these data suggest that specific phosphorylation of Mre11 is induced by DNA damage and NBS1 is essential in this process, perhaps by recruiting specific kinases. We are currently focusing on identifying and deciphering the signaling systems and kinases responsible for critical regulatory events in DNA double-strand break repair.
ScRad9 was the first checkpoint protein to be identified. Mutation of the scRad9 prevents scRad53 activation upon DNA damage. To date, a mammalian homologue of scRad9 has not been identified. From the close homology of their BRCT motifs, we predict that BRCA1, 53BP1, and NFBD1 are the candidate homologues for scRad9 in mammals. Based on the yeast studies, we also predict that these molecules function in the DNA checkpoint. Potential roles of BRCA1 and 53BP1 in DNA damage checkpoint control have been suggested. We have recently showed that NFBD1 is associated with nuclear foci that are induced by various DNA-damaging agents. These foci colocalize with phosphorylated H2AX. BRCT motifs of NFBD1 are required for its foci formation. These observations suggest that NFBD1 is also involved in DNA damage-signaling pathways in mammalian cells. Since BRCA1 plays dual roles in response to DNA damage, we predict that both 53BP1 and NFBD1 may also have roles in DNA damage repair and checkpoint control. We plan to explore these possibilities by establishing the network of molecules involved with 53BP1 and NFBD1 in DNA repair and checkpoint control. We will use genetic approaches to establish direct evidence to confirm or refute our hypotheses.
Trainees will study the biological and biochemical functions of tumor suppressor genes and DNA repair machinery and will gain experience in mammalian genetics, biochemistry, molecular biology and cell biology.
Selected Publications:
Chen, P.-L., Scully, P., Shew, J.-Y., Wang, J.-Y.J., and Lee, W.-H. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell 58: 1193-1198, 1989.
Chen, P.-L., Chen, Y., Bookstein, R., and Lee, W.-H. Genetic mechanisms of tumor suppression by the human p53 gene. Science250: 1576-1580, 1990.
Chen, P.-L., Chen, Y., Shan, B., Bookstein, R., and Lee, W.-H. Stability of retinoblastoma gene expression determines the tumorigenicity of reconstituted retinoblastoma cells. Cell Growth Differ. 3: 119-125, 1992.
Chen, P.-L., Riley, D., and Lee, W.-H. The retinoblastoma protein as a fundamental mediator of growth and differentiation signals. Crit. Rev. Eukaryot. Gene Exp. 5: 79-95, 1995.
Chen, P.-L., Riley, D., Chen-Kiang, S., and Lee, W.-H. Retinoblastoma protein directly interacts with and activates the transcription factor NF-IL6. Proc. Natl. Acad. Sci. USA 93: 465-470, 1996.
Chen, P.-L., Riley, D.J., Chen, Y., and Lee, W.-H. Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs.Genes Dev. 10: 2794-2804, 1996.
Chen, P.-L., Chen, C.-F., Chen, Y., Xiao, J., Sharp, Z.D., and Lee, W.-H. The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc. Natl. Acad. Sci. USA 95: 5287-5292, 1998.
Dong, Z., Zhong, Q., and Chen, P.-L. The NBS protein is essential for MRE11 phosphorylation upon DNA damage. J. Biol. Chem. 274: 19513-19516, 1999.
Chen, C.-F., Chen, P.-L., Zhong, Q., Sharp, Z.D., and Lee, W.-H. Expression of BRC repeats in breast cancer cells disrupts the BRCA2-Rad51 complex and leads to radiation hypersensitivity and loss of G2/M checkpoint control. J. Biol. Chem. 274: 32931-32935, 1999.
Li, S., Ting, N. S.Y., Zheng, L., Chen, P.-L., Ziv, Y., Shiloh, Y., Lee, E. Y-H, and Lee, W-H. Functional link of BRCA1 and ataxia-telangiectasia gene product in DNA damage response. Nature 406: 210-215, 2000.
Zheng, L., Pan, H., Li, S., Flesken-Nikitin, A., Chen, P-L., Boyer, T., and Lee, W-H. Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein. Mol. Cell. 6: 757-768, 2000.
Wu, G., Lee, W.-H., and Chen, P.-L. NBS1 and TRF1 colocalize at PML bodies during late S/G2 phases in immortalized telomerase-negative cells: Implication of NBS1 in alternative lengthening of telomeres. J. Biol. Chem. 275: 30618-30622, 2000.
Shang YL, Bodero AJ, Chen P-L: NFBD1, a novel nuclear protein with signature motifs of FHA and BRCT, and an internal 41 amino acid repeat sequence, is an early participant in DNA damage response. J Biol Chem. 278:6323-6329, 2003.
Peng A, and Chen P-L: NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage. J Biol Chem. 278:8873-8876, 2003.
Wu G, Jiang X, Lee WH and Chen P-L: Assembly of functional ALT-associated promyelocytic leukemia bodies requires Nijmegen Breakage Syndrome 1. Cancer Res. 63:2589-2595, 2003.
