Although metastasis-associated protein 1 (MTA1), a component of the nucleosome remodeling and deacetylase (NuRD) complex, is a DNA-damage response protein and regulates p53-dependent DNA repair, it remains unknown whether MTA1 also participates in p53-independent DNA damage response. Here, we provide evidence that MTA1 is a p53-independent transcriptional corepressor of p21(WAF1), and the underlying mechanism involves recruitment of MTA1-histone deacetylase 2 (HDAC2) complexes onto two selective regions of the p21(WAF1) promoter. Accordingly, MTA1 depletion, despite its effect on p53 down-regulation, superinduces p21(WAF1), increases p21(WAF1) binding to proliferating cell nuclear antigen (PCNA), and decreases the nuclear accumulation of PCNA in response to ionizing radiation. In support of a p53-independent role of MTA1 in DNA damage response, we further demonstrate that induced expression of MTA1 in p53-null cells inhibits p21(WAF1) promoter activity and p21(WAF1) binding to PCNA. Consequently, MTA1 expression in p53-null cells results in increased induction of gamma H2AX foci and DNA double strand break repair, and decreased DNA damage sensitivity following ionizing radiation treatment. These findings uncover a new target of MTA1 and the existence of an additional p53-independent role of MTA1 in DNA damage response, at least in part, by modulating the p21(WAF1)-PCNA pathway, and thus, linking two previously unconnected NuRD complex and DNA-damage response pathways.