Structural Biology of MDC1, a Novel Checkpoint Mediator

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DESCRIPTION (provided by applicant): Since the loss of genomic integrity is one of the hallmarks of cancer, the success of our efforts to prevent cancer lies in our ability to understand how cells maintain the fidelity of the genome in the face of DNA replication errors and challenges to the chemical stability of DNA by both intracellular and extracellular agents. Cells have evolved complex regulatory networks called checkpoints to sense DNA damage and coordinate DNA repair, DNA replication, and cell-cycle progression. The novel protein MDC1 (Mediator of DNA Damage Checkpoint protein 1) recently emerged as a critical player during the cellular response to DNA damage because it is necessary for the ATM kinase to transmit DNA damage signals to the checkpoint machinery. The goal of this research is to provide structural insight into the molecular mechanisms of cellcycle checkpoint control. We hypothesize that the modular architecture of MDC1 allows it to act as a molecular hub to mediate the DNA damage response through multiple dynamic and stable protein-protein interactions. We propose a multi-tiered approach to determine the structural biochemistry of MDC1 by combining biochemistry with both low- and high-resolution biophysical techniques.