Maintenance of genomic stability is critical for the well-being of organisms. To maintain genomic stability, cells have developed a network of signaling pathways, collectively known as the DNA damage response (DDR) pathway, to sense and repair DNA damage. In response to DNA damage, many factors involved in the DDR, such as MDC1, 53BP1, and BRCA1 get recruited to the sites of DNA damage to facilitate cell cycle checkpoint activation and DNA repair. We and others have studied the molecular mechanisms by which BRCA1, 53BP1 and NBS1 are recruited to the sites of DNA damage through MDC1. More recently, we found that disassembly of DDR factors including MDC1 is also important for proper DDR. These observations led us to hypothesize that dynamic assembly and disassembly of MDC1/RNF8/BRCA1/53BP1 is critical for the maintenance of genomic stability. In our preliminary data, we found that several E3 ubiquitin ligases play an important role in this process. We found that RNF4 and PHRF1 negatively regulate the accumulation of MDC1 and RNF8 respectively. We plan to further test our hypothesis with the following Specific Aims:
Aim 1. Study the mechanism of cell cycle specific removal of MDC1by RNF4.
Aim 2. Study the regulation of the MDC1-RNF8 pathway by PHRF1.
Aim 3. Study the role of PHRF1 in tumorigenesis using animal models. The proposed studies are an underexplored area in the field DNA damage response. We believe that successful completion of these studies will significantly advance our understating of the temporal and spatial regulation of DDR. In addition, RNF4 and PHRF1 are all found to be misregulated in human cancers. Our studies could also reveal important insight into molecular oncogenesis and cancer therapy.
Defective DNA damage response pathway is linked to tumorigenesis. Therefore, understanding the DNA damage response pathway will help us understand how cancer arises and how to prevent it. In addition, given that many cancer therapies involve DNA damage-inducing agent, a detailed understanding of the DNA damage response pathway and its defects in cancer cells will help us to design targeted therapy for specific cancers.
|Deng, Min; Yang, Xu; Qin, Bo et al. (2016) Deubiquitination and Activation of AMPK by USP10. Mol Cell 61:614-24|
|Kim, Jung Jin; Lee, Seung Baek; Yi, Sang-Yeop et al. (2016) WSB1 overcomes oncogene-induced senescence by targeting ATM for degradation. Cell Res :|
|Zhang, Haoxing; Liu, Hailong; Chen, Yali et al. (2016) A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice. Nat Commun 7:10201|
|Wang, Zhiquan; Zhang, Honglian; Liu, Ji et al. (2016) USP51 deubiquitylates H2AK13,15ub and regulates DNA damage response. Genes Dev 30:946-59|
|Liu, Tongzheng; Fang, Yuan; Zhang, Haoxing et al. (2016) HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy. Cancer Res 76:572-81|
|Evans, Debra L; Zhang, Haoxing; Ham, Hyoungjun et al. (2016) MMSET is dynamically regulated during cell-cycle progression and promotes normal DNA replication. Cell Cycle 15:95-105|
|Oi, N; Yuan, J; Malakhova, M et al. (2015) Resveratrol induces apoptosis by directly targeting Ras-GTPase-activating protein SH3 domain-binding protein 1. Oncogene 34:2660-71|
|Qin, Bo; Minter-Dykhouse, Katherine; Yu, Jia et al. (2015) DBC1 functions as a tumor suppressor by regulating p53 stability. Cell Rep 10:1324-34|
|Pokorny, Jenny L; Calligaris, David; Gupta, Shiv K et al. (2015) The Efficacy of the Wee1 Inhibitor MK-1775 Combined with Temozolomide Is Limited by Heterogeneous Distribution across the Blood-Brain Barrier in Glioblastoma. Clin Cancer Res 21:1916-24|
|Luo, Kuntian; Deng, Min; Li, Yunhui et al. (2015) CDK-mediated RNF4 phosphorylation regulates homologous recombination in S-phase. Nucleic Acids Res 43:5465-75|
Showing the most recent 10 out of 33 publications