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.
|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|
|Pei, Huadong; Wu, Xiaosheng; Liu, Tongzheng et al. (2013) The histone methyltransferase MMSET regulates class switch recombination. J Immunol 190:756-63|
|Qin, Bo; Gao, Bowen; Yu, Jia et al. (2013) Ataxia telangiectasia-mutated- and Rad3-related protein regulates the DNA damage-induced G2/M checkpoint through the Aurora A cofactor Bora protein. J Biol Chem 288:16139-44|
|Yuan, Jian; Luo, Kuntian; Liu, Tongzheng et al. (2012) Regulation of SIRT1 activity by genotoxic stress. Genes Dev 26:791-6|
|Luo, Kuntian; Yuan, Jian; Lou, Zhenkun (2011) Oligomerization of MDC1 protein is important for proper DNA damage response. J Biol Chem 286:28192-9|
|Pei, Huadong; Zhang, Lindsey; Luo, Kuntian et al. (2011) MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 470:124-8|
|Ichijima, Yosuke; Ichijima, Misako; Lou, Zhenkun et al. (2011) MDC1 directs chromosome-wide silencing of the sex chromosomes in male germ cells. Genes Dev 25:959-71|
|Yuan, Jian; Luo, Kuntian; Zhang, Lizhi et al. (2010) USP10 regulates p53 localization and stability by deubiquitinating p53. Cell 140:384-96|
|Luo, Kuntian; Yuan, Jian; Chen, Junjie et al. (2009) Topoisomerase IIalpha controls the decatenation checkpoint. Nat Cell Biol 11:204-10|
|Minter-Dykhouse, Katherine; Ward, Irene; Huen, Michael S Y et al. (2008) Distinct versus overlapping functions of MDC1 and 53BP1 in DNA damage response and tumorigenesis. J Cell Biol 181:727-35|
Showing the most recent 10 out of 11 publications