THE REDOX DNA REPAIR PROTEIN, REF-1, IS ESSENTIAL FOR EARLY EMBRYONIC-DEVELOPMENT IN MICE/

The DNA binding activity of AP-1 proteins is modulated, in vitro, by a posttranslational mechanism involving reduction oxidation, This mode of regulation has been proposed to control both the transcriptional ac tivity and the oncogenic potential of Fos and Jun. Previous studies re vealed that reduction of oxidized Fos and Jun by a cellular protein, R ef-l, stimulates sequence-specific AP-1 DNA-binding activity, Ref-l, a bifunctional protein, is also capable of initiating the repair of apu rinic/apyrymidinic sites in damaged DNA, The relationship between the redox and DNA repair activities of Ref-l is intriguing; both activitie s have been suggested to play an important role in the cellular respon se to oxidative stress. To investigate the physiological function of R ef-1, we used a gene targeting strategy to generate mice lacking a fun ctional ref-l gene. We report here that heterozygous mutant mice devel op into adulthood without any apparent abnormalities. In contrast, hom ozygous mutant mice, Lacking a functional ref-l; gene, die during embr yonic development, Detailed analysis indicates that death occurs follo wing blastocyst formation, shortly after the time of implantation. Deg eneration of the mutant embryos is clearly evident at embryonic day 5. 5. These findings demonstrate that Ref-l is essential for early embryo nic development.