Flap endonuclease 1 and its role in eukaryotic DNA metabolism

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Abstract

Flap endonuclease 1 (FEN1) is strongly specific for the substrate structure. The natural substrates of FEN1 are 5′-flap structures formed by three DNA strands one of which has an unpaired 5′ portion (a flap). Flap structures occur as intermediates in various processes of DNA metabolism such as DNA replication, Okazaki fragment maturation during replication of the lagging strand, and strand displacement DNA synthesis in base excision repair. In addition, FEN1 possesses 5′-exonuclease activity and gap endonuclease activity, discovered recently. FEN1 physically and functionally interacts with many DNA replication and repair proteins, including the proliferating cell nuclear antigen, helicase/nuclease Dna2, WRN, BLM, replication protein A, apurinic/apyrimidinic endonuclease 1, DNA polymerase β, poly(ADP-ribose) polymerase 1, high mobility group protein 1, human immunodeficiency virus integrase, transcriptional coactivator p300, chromatin proteins, cyclin-dependent kinases (Cdk1 and Cdk2), and cyclin A. FEN1 activity is important for maintaining the integrity of repetitive sequences in the genome. Recent data suggest a correlation between defects in hFEN1 activity and the development and progression of neurodegenerative diseases and cancer. Hence, FEN1 exerts a dramatic effect on cell growth and development and, consequently, attracts particular interest.

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