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Homeodomain Interacting Protein Kinase-2 (HIPK2) is a protein with many functions and a modulator of p53 oncosuppressor functions. TP53 is the "guardian of the genome" thus, is the most critical tumor suppressor gene product that inhibits malignant transformation. P53R2 gene is directly induced by p53 in response to DNA damage and is involved in the p53 checkpoint for repairing damaged DNA to block genome instability. Here we wanted to explore the involvement of HIPK2 in damaged-DNA repair by regulating p53-induced p53R2 gene. We show that, induction of p53R2 expression, p53 recruitment onto p53R2 promoter, and its transcriptional activation was strongly impaired by HIPK2 knock-down, in response to drug. The failure of p53-induced p53R2 activation markedly compromised damaged-DNA repair efficiency. Finally, overexpression of exogenous p53 overcame the inability of endogenous p53 to activate p53R2-luc promoter in HIPK2 depleted cells. These data suggest that HIPK2 is involved in damaged-DNA repair taking part in restraining tumor progression, at least in part depending on p53 regulation.