DNA damage response is critically important for the maintenance of genomic integrity and tumor suppression. A key player involved in DNA damage response is MDC1, the Mediator of DNA damage Checkpoint protein 1. Over the years, we have shown that MDC1 acts downstream of H2AX phosphorylation and is involved in the regulation of many ATM-dependent events. More recently, we demonstrated that MDC1 also initiates a RNF8 and ubiquitination-dependent signaling pathway, which is required for the accumulation of many DNA damage checkpoint and repair proteins at sites of DNA breaks. We now know that the regulation of this ubiquitination-dependent cascade is quite dynamic, since an ubiquitin specific protease USP3 can counteract RNF8 function and remove ubiquitin moiety from histones. Such ubiquitination and deubiquitination cycle controlled by RNF8 and USP3 may be involved in DNA damage signal transduction. In addition, we have isolated TopBP1 as a new MDC1-associated protein. Since TopBP1 is mostly known for its role in replication stress pathway and its direct involved in the activation of ATR kinase, we reason that MDC1 may have a previously uncharacterized role in replication checkpoint control. It may stabilize TopBP1 at stalled replication forks, act to amply replication stress signals and thus enhance ATR activation and replication checkpoint control. Based on these preliminary studies, we propose to: 1) study MDC1 function in replication checkpoint control;2) investigate the roles of USP3 in DNA damage response;3) determine the functional significance of RNF8/USP3-dependent pathway in DNA damage repair and tumorigenesis in vivo.

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MDC1 (Mediator of DNA damage checkpoint protein 1) is a key DNA damage checkpoint protein, which we identified and studied for several years. We now know that MDC1 controls multiple signaling pathways involved in DNA damage response. Further studies of MDC1 functions in DNA damage response will allow us to understand the complexity of DNA damage signaling pathways and how cells utilize multiple redundant and overlapping pathways to ensure genomic integrity.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Molecular Oncogenesis Study Section (MONC)
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Pelroy, Richard
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University of Texas MD Anderson Cancer Center
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Zhang, Aili; Peng, Bo; Huang, Ping et al. (2017) The p53-binding protein 1-Tudor-interacting repair regulator complex participates in the DNA damage response. J Biol Chem 292:6461-6467
Li, Xu; Wang, Wenqi; Xi, Yuanxin et al. (2016) FOXR2 Interacts with MYC to Promote Its Transcriptional Activities and Tumorigenesis. Cell Rep 16:487-497
Lee, Yuan-Cho; Zhou, Qing; Chen, Junjie et al. (2016) RPA-Binding Protein ETAA1 Is an ATR Activator Involved in DNA Replication Stress Response. Curr Biol 26:3257-3268
Li, Nan; Feng, Lin; Liu, Hui et al. (2016) PARP Inhibition Suppresses Growth of EGFR-Mutant Cancers by Targeting Nuclear PKM2. Cell Rep :
Wang, Wenqi; Li, Xu; Lee, Moonsup et al. (2015) FOXKs promote Wnt/?-catenin signaling by translocating DVL into the nucleus. Dev Cell 32:707-18
Wang, Wenqi; Xiao, Zhen-Dong; Li, Xu et al. (2015) AMPK modulates Hippo pathway activity to regulate energy homeostasis. Nat Cell Biol 17:490-9
Li, Xu; Wang, Wenqi; Chen, Junjie (2015) From pathways to networks: connecting dots by establishing protein-protein interaction networks in signaling pathways using affinity purification and mass spectrometry. Proteomics 15:188-202
Wang, Wenqi; Li, Nan; Li, Xu et al. (2015) Tankyrase Inhibitors Target YAP by Stabilizing Angiomotin Family Proteins. Cell Rep 13:524-532
Wang, Jiadong; Aroumougame, Asaithamby; Lobrich, Markus et al. (2014) PTIP associates with Artemis to dictate DNA repair pathway choice. Genes Dev 28:2693-8
Li, Yujing; Fong, Ka-Wing; Tang, Mengfan et al. (2014) Fam118B, a newly identified component of Cajal bodies, is required for Cajal body formation, snRNP biogenesis and cell viability. J Cell Sci 127:2029-39

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