Zhiyuan Shen
Professor

Genomic stability and molecular cancer etiology, DNA repair and homologous recombination, Modulation of cell response to therapeutic DNA damage

Maintenance of genomic stability and prevention of tumorigenesis by precisely regulated homologous recombination (HR) - Genomic instability is a major driving force for tumorigenesis. Mammalian cells use several mechanisms to maintain their genomic stability, including high fidelity DNA replication in S-phase, accurate chromosome segregation in M-phase, precise and error-free repair of DNA damage throughout the cell cycle, and precise cell cycle coordination. HR often precisely repairs DNA double strand breaks, and restarts stalled replication forks to ensure the fidelity of DNA replication and to enable accurate chromosome segregation in mitosis. Thus mis-regulation of HR is a major source of genomic instability. At least four types of HR mis-regulation may occur:
1) HR often uses a sister-chromatid (or a highly homologous region) as the template for DNA repair, and is historically considered an error-free DNA repair pathway. When HR is inhibited, cells may use alternative repair pathways that are more error-prone. Thus, reduced HR is considered a risk factor for tumorigenesis.
2) Mis-resolution of HR DNA intermediates may increase product errors, leading to genomic instability.
3) On the other hand, non-restricted HR may enable recombination between similar sequences, such as repeat sequences of the human genome. This increases the risk of regional chromosome rearrangements, which is a form of genomic instability.
4) HR is highly coordinated with other cellular processes, such as DNA replication, mitosis, and cell cycle regulation. Mis-coordination of HR with cell cycle is expected to be a major source of HR-related genomic instability.
We are interested in how HR is regulated, and coordinated with other cellular processes such as cell cycle regulation and mitosis. We address this issue by examining the functions of proteins that may regulate both HR and cell cycle control. One such protein is BCCIP (BRCA2 and CDKN1A Interacting Protein). Our works have shown that BCCIP regulates HR, cell cycle, and mitosis. Alterations of BCCIP have been implicated in many forms of human cancer. Currently, biochemical, cell and molecular biology, and transgenic approaches are being used to further characterize BCCIP functions and biochemical activities, and its roles in tumorigenesis.

Modulation of cell response to therapeutic DNA damage - Upon DNA damage, three potential outcomes are expected: cell death, survival with full recovery of damaged DNA, or survival with alternations in the genome. The ultimate goal for DNA damage based cancer therapy is to maximize cancer cell death, minimize death of normal cells, and minimize survival with genomic alterations for cancer and normal cells. These outcomes are dictated by two major factors: 1) the initial level of DNA damage received by each cell types; and 2) an intrinsic network of DNA damage response within the cells. This network of DNA damage response includes signal transduction, gene expression regulation, DNA repair, cell cycle checkpoints, and regulation of cell death pathway. After a comprehensive understanding on the mechanism of action for this network, it is possible to modulate this network to favor cancer cell death, while protecting normal cells. We are interested in developing strategies to modulate the cell responses to DNA damage to increase cancer treatment efficacy while reducing side effects. Cell based screen systems are being developed to identify drug targets and drugs to sensitize cancer to therapeutic DNA damage. We are also interested in identifying markers that may predict clinical outcomes of therapeutic DNA damage.

Selected Publications

Du Y, Zhou J, Fan J, Shen Z, Chen X. (2009) Streamline proteomic approach for characterizing protein-protein interaction network in a RAD52 protein complex. J Proteome Res. 8(5):2211-2217.

Rewari A, Lu H, Parikh R, Yang Q, Shen Z, Haffty BG. (2008) BCCIP as a prognostic marker for radiotherapy of laryngeal cancer. Radiother Oncol. 90(2):183-8.

Meng X, Fan J, and Shen Z. (2007) Roles of BCCIP in chromosome stability and cytokinesis. Oncogene 26(43):6253-6260.

Wray J, Liu J, Nickoloff JA, Shen Z. (2008) Distinct RAD51 associations with RAD52 and BCCIP in response to DNA damage and replication stress. Cancer Res. 68(8):2699-707.

Lu H, Yue J, Meng X, Nickoloff JA, Shen Z. (2007) BCCIP regulates homologous recombination by distinct domains and suppresses spontaneous DNA damage. Nucleic Acids Res. 35(21):7160-70.

Meng, X., and Shen, Z. (2006) Abrogation of the transactivation activity of p53 by BCCIP down-regulation, J. Biol. Chem. 282(3): 1570-1576.

Shen, Z., and Nickoloff, JA. (2006) Mammalian homologous recombination repair and cancer intervention. Chapter 5 in “DNA Repair, Genetic Instability, and Cancer”, World Scientific Publishing Co. Pte. Ltd., Singapore.

Lu, H., Guo, X., Meng, X., Liu, J., Allen, C., Wray, J., Nickoloff, J.A., and Shen, Z (2005) The BRCA2-Interacting Protein BCCIP functions in RAD51 and BRCA2 focus formation and homologous recombinational Repair. Mol. Cell. Biol. 25(5):1949-1957

Meng, X., Yuan, Y., Maestas, A., and Shen, Z. (2004) Recovery from DNA damage-induced G2-arrest requires the actin binding protein filamin-A/ABP-280. J Biol Chem 279:6098-6105.

Meng, X., Liu, J., and Shen, Z. (2004) Inhibition of G1 to S Cell cycle progression by BCCIPbeta. Cell Cycle 3:343-357.

Yuan, Y., and Shen, Z. (2001) Interaction with BRCA2 suggests a role of filamin-A (hsFLNa) in DNA damage response. J. Biol. Chem. 276: 48318-48324.

Liu, J. Yuan, Y. Huan, J. and Shen, Z. (2001) Inhibition of brain and breast cancer cell growth by BCCIPalpha, an evolutionarily conserved nuclear protein that interacts with BRCA2. Oncogene 20:336-35.