MLL5 has been implicated in multiple aspects of cell physiology such as hematopoiesis, cell cycle control and chromatin regulatory network.In this study we present evidence that MLL5 is involved in the camptothecin-induced p53 activation.Carnptothecin promoted the degradation of MLL5 protein in a time-and dose-dependent manner in actively replicating cells.The down-regulation of MLL5 led to phosphorylation of p53 at Ser392, which was abrogated by exogenous over-expression of MLL5.In MLL5-knockdown cells, p53 protein was stabilized and bound to DNA with higher affinity, leading to activation of downstream genes.