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Volume 271, Number 47, Issue of November 22, 1996 pp. 29624-29631
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

Mechanism of Tracking and Cleavage of Adduct-damaged DNA Substrates by the Mammalian 5'- to 3'-Exonuclease/Endonuclease RAD2 Homologue 1 or Flap Endonuclease 1

(Received for publication, June 25, 1996, and in revised form, September 4, 1996)

Carole J. Barnes Dagger , Alan F. Wahl § , Binghui Shen , Min S. Park and Robert A. Bambara Dagger

From the Dagger  Department of Biochemistry and Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, § Growth Regulation Department, Bristol-Myers Squibb Pharmaceutical, Seattle, Washington 98121, and  Life Science Division, Los Alamos National Laboratory, Los Alamos, New Mexico 87545

The mammalian 5'- to 3'-exonuclease/endonuclease, called RAD2 homologue 1 or flap endonuclease 1, has a unique cleavage activity, dependent on specific substrate structure. On a primer-template, in which the primer has an unannealed 5'-tail, endonucleolytic cleavage near the annealing point releases the tail intact. Entering at the 5'-end, the nuclease tracks along the entire tail to the point of cleavage. Genetic analyses suggest that this nuclease removes DNA adducts in vivo (Sommers, C. H., Miller, E. J., Dujon, B., Prakash, S., and Prakash, L. (1995) J. Biol. Chem. 270, 4193-4196). Micrococcal nuclease footprinting shows that after tracking the nuclease protects a region of the tail 25 nucleotides long, adjacent to the cleavage site.

Substrates with adducts at specific locations were used to assess the mechanism of RAD2 homologue 1 nuclease tracking and its ability to cleave modified DNA. Either a conventional cis-diamminedichloroplatinum (II) (CDDP) or a bulky CDDP derivative was placed within or beyond the region protected by the nuclease. The nuclease cleaved the tail of both substrates. In contrast, a CDDP adduct just adjacent to the expected cleavage point was inhibitory. A CDDP adduct at the very 5'-end of the tail was also cleaved. The nuclease could remove tails containing adducts on the sugar-phosphate backbone. Apparently, the nuclease is designed to slide over various types of damage on single stranded DNA and then cut past the damaged site.


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