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NFBD1/MDC1 is a large nuclear protein with an anti-apoptotic potential which participates in DNA damage response. Recently, we have demonstrated that NFBD1 has an inhibitory effect on pro-apoptotic p53 and DNA damage-induced transcriptional repression of NFBD1 plays an important role in p53-dependent apoptotic response. In this study, we have found that NFBD1 promoter region contains canonical Sp1-, STAT-1- and NF-Y-binding sites and finally we have identified Sp1 as a transcriptional activator for NFBD1. The 5′-RACE and bioinformatic analyses revealed that NFBD1 encodes at least four transcriptional variants arising from distinct transcriptional start sites. Luciferase reporter assays using a series of NFBD1 promoter deletion mutants demonstrated that the proximal Sp1-binding site is required for the transcriptional activation of NFBD1. Indeed, the endogenous Sp1 was recruited onto the proximal Sp1-binding site as examined by chromatin immunoprecipitation (ChIP) assay and siRNA-mediated knockdown of the endogenous Sp1 in HeLa cells reduced the expression levels of NFBD1, which renders cells sensitive to adriamycin (ADR). In support of this notion, mithramycin A (MA, Sp1 inhibitor) treatment resulted in a significant down-regulation of NFBD1. Taken together, our present findings suggest that Sp1-mediated transcriptional regulation of NFBD1 plays an important role in the regulation of DNA damage response.