| Summary: | 博士 === 國立臺灣大學 === 微生物學研究所 === 104 === MDM2 is an E3 ubiquitin ligase that targets proteins involved in cell cycle progression. Although many MDM2 substrates have been identified, how its activity is regulated is not fully understood, especially when cells are under oxidative stress. Here we show that upon oxidative stress, MDM2 can be phosphorylated by human Mps1 (hMps1)/TTK, a kinase known to function in the spindle assembly and DNA damage checkpoints. Consequently, MDM2-mediated H2B ubiquitination is enhanced, and Ala substitution at the hMps1/TTK phosphorylation sites compromises this effect. In cells, H2B ubiquitination was enhanced upon oxidative stress. Depletion of hMps1/TTK or MDM2 not only abrogated this induction but also resulted in reduced DNA repair, cell survival, and ATR signaling. Consistent with these observations, cells expressing a ubiquitination-deficient H2B mutant were also defective in DNA repair and ATR signaling. Complementation with WT MDM2 but not the phospho-deficient mutant rescued the H2B ubiquitination and DNA repair, suggesting the requirement for hMps1/TTK-mediated MDM2 phosphorylation. Taken together, we propose that hMps1/TTK phosphorylates MDM2 upon oxidative damage to promote H2B ubiquitination, which in turn facilitates oxidative DNA damage signaling and repair.
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