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Sp1‐mediated transcriptional regulation of NFBD1/MDC1 plays a critical role in DNA damage response pathway
Author(s) -
Bu Youquan,
Suenaga Yusuke,
Ono Sayaka,
Koda Tadayuki,
Song Fangzhou,
Nakagawara Akira,
Ozaki Toshinori
Publication year - 2008
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2007.01144.x
Subject(s) - biology , dna damage , microbiology and biotechnology , dna , computational biology , genetics
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.