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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA130996-03
Application #
7848881
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Pelroy, Richard
Project Start
2008-07-01
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$313,533
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Yu, Jia; Qin, Bo; Wu, Fengying et al. (2017) Regulation of Serine-Threonine Kinase Akt Activation by NAD+-Dependent Deacetylase SIRT7. Cell Rep 18:1229-1240
Kim, Jung Jin; Lee, Seung Baek; Yi, Sang-Yeop et al. (2017) WSB1 overcomes oncogene-induced senescence by targeting ATM for degradation. Cell Res 27:274-293
Li, Jun; Bonkowski, Michael S; Moniot, S├ębastien et al. (2017) A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science 355:1312-1317
Liu, Tongzheng; Yu, Jia; Deng, Min et al. (2017) CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1. Nat Commun 8:13923
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
Luo, Kuntian; Li, Lei; Li, Yunhui et al. (2016) A phosphorylation-deubiquitination cascade regulates the BRCA2-RAD51 axis in homologous recombination. Genes Dev 30:2581-2595
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
Lee, SeungBaek; She, Jun; Deng, Bo et al. (2016) Multiple-level validation identifies PARK2 in the development of lung cancer and chronic obstructive pulmonary disease. Oncotarget 7:44211-44223
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

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