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Papers In Press, published online ahead of print September 12, 2001
J. Biol. Chem, 10.1074/jbc.M106423200
Submitted on July 9, 2001
Revised on September 11, 2001
Accepted on September 12, 2001
Cancer Cell Biology, Harvard School of Public Health, Boston, MA 02115
Corresponding Author: bdemple{at}hsph.harvard.edu
Abasic (apurinic/apyrimidinic or AP) sites are a frequent type of DNA damage that threaten genetic stability. The predominant mammalian enzyme initiating repair of AP sites is the Ape1 AP endonuclease (also called Apex or Hap1), which also facilitates DNA binding by several transcription factors (Ref1 activity). We found that expression of the APE1 gene was coordinated with the cell cycle in murine NIH3T3 cells: APE1 mRNA levels rose after the G1-S transition and peaked ~4-fold higher in early- to mid-S-phase. The increased APE1 mRNA was due to transcriptional activation rather than increased mRNA stability. Fusions of various APE1 promoter fragments to the CAT reporter gene indicated that APE1 expression depends on two transcription factor Sp1 binding sites within the promoter region. Mutation of these sites or of two CCAAT elements within the APE1 promoter, in conjunction with protein binding studies, demonstrated their specific roles. The Sp1 site upstream of the transcription start, together with an adjacent CCAAT element, establishes a protein-DNA complex required for basal transcription of APE1. The Sp1 site downstream of the transcription start was required for the response to cell growth. Since Ape1 is a dual function enzyme, its cell cycle-dependent expression might affect both DNA repair and the activity of various transcription factors as a function of the cell cycle.
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