Human Molecular Genetics, Vol 8, 2263-2273, Copyright © 1999 by Oxford University Press
AL Greene, JR Snipe, DA Gordenin and MA Resnick
The flap endonuclease, FEN1, is an evolutionarily conserved component of
DNA replication from archaebacteria to humans. Based on in vitro results,
it processes Okazaki fragments during replication and is involved in base
excision repair. FEN1 removes the last primer ribonucleotide on the lagging
strand and it cleaves a 5' flap that may result from strand displacement
during replication or during base excision repair. Its biological
importance has been revealed largely through studies in the yeast
Saccharomyces cerevisiae where deletion of the homologous gene RAD27
results in genome instability and mutagen sensitivity. While the in vivo
function of Rad27 has been well characterized through genetic and
biochemical approaches, little is understood about the in vivo functions of
human FEN1. Guided by our recent results with yeast RAD27, we explored the
function of human FEN1 in yeast. We found that the human FEN1 protein
complements a yeast rad27 null mutant for a variety of defects including
mutagen sensitivity, genetic instability and the synthetic lethal
interactions of a rad27 rad51 and a rad27 pol3-01 mutant. Furthermore, a
mutant form of FEN1 lacking nuclease function exhibits dominant-negative
effects on cell growth and genome instability similar to those seen with
the homologous yeast rad27 mutation. This genetic impact is stronger when
the human and yeast PCNA-binding domains are exchanged. These data indicate
that the human FEN1 and yeast Rad27 proteins act on the same substrate in
vivo. Our study defines a sensitive yeast system for the identification and
characterization of mutations in FEN1.
ARTICLES
Functional analysis of human FEN1 in Saccharomyces cerevisiae and its role in genome stability
Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, PO Box 12233, Research Triangle Park, NC 27709, USA
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