Maintenance of genomic stability is critical for the well-being of organisms. To maintain genomic stability, cells have developed a network of signaling pathways called the DNA damage response pathway to sense and repair DNA damage. We and others have shown that MDC1 (Mediator of DNA Damage Checkpoint Protein 1, previously known as Kiaa0170), a previously uncharacterized protein, regulates various aspects of the DNA damage response pathway. We have also generated MDC1 knockout mice and shown that cells deficient in MDC1 display genomic instability. These observations support our central hypothesis that MDC1 maintains genomic stability by mediating and facilitating signal transduction pathways following genotoxic stress. We plan to further explore the mechanism of how MDC1 maintains genomic stability. In addition, we will examine the role of MDC1 in tumor suppression using the MDC1 knockout mouse as an animal model.
The specific aims are: 1. Explore the biological significance of ATM-dependent phosphorylation of MDC1. We have mapped an ATM phosphorylation site on MDC1, and our preliminary results suggest that this phosphorylation site is involved in the cell cycle checkpoint activation. We will further explore the regulation and functional significance of this phosphorylation site. 2. Investigate the MDC1-topoisomerase II interaction. Our preliminary results suggest that the BRCT domain of MDC1 interacts with phospho-Ser1524 of topoisomerase II, and this interaction regulates the decatenation checkpoint. We will further investigate the regulation of the MDC1-topoisomerase II interaction, and how it regulates the decatenation checkpoint and genomic stability. 3. Investigate the role of genomic instability in aging and tumorigenesis. Genomic instability has been linked to both premature aging and tumorigenesis. We will further evaluate whether loss of MDC1 results in premature aging and tumorigenesis in MDC1-/- mice. Results from these studies will provide new molecular mechanisms of the maintenance of genomic stability and the prevention of aging and tumorigenesis.
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