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Molecular and Cellular Biology, February 1999, p. 1126-1135, Vol. 19, No. 2
Department of Pathology, Stanford University
School of Medicine, Stanford, California 94305-5324
Received 29 July 1998/Returned for modification 14 September
1998/Accepted 5 November 1998
We have identified thermosensitive mutants of five
Schizosaccharomyces pombe replication proteins that have
a mutator phenotype at their semipermissive temperatures.
Allele-specific mutants of DNA polymerase
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Mutator Phenotype Induced by Aberrant
Replication
(pol
) and
mutants of Pol
, two Pol
subunits, and ligase exhibited increased
rates of deletion of sequences flanked by short direct repeats.
Deletion of rad2+, which encodes a nuclease
involved in processing Okazaki fragments, caused an increased rate of
duplication of sequences flanked by short direct repeats. The deletion
mutation rates of all the thermosensitive replication mutators
decreased in a rad2
background, suggesting that deletion
formation requires Rad2 function. The duplication mutation rate of
rad2
was also reduced in a thermosensitive polymerase background, but not in a ligase mutator background, which suggests that
formation of duplication mutations requires normal DNA
polymerization. Thus, although the deletion and duplication mutator
phenotypes are distinct, their mutational mechanisms are
interdependent. The deletion and duplication replication mutators all
exhibited decreased viability in combination with deletion of a
checkpoint Rad protein, Rad26. Interestingly, deletion of Cds1, a
protein kinase functioning in a checkpoint Rad-mediated reversible
S-phase arrest pathway, decreased the viability and exacerbated the
mutation rate only in the thermosensitive deletion replication mutators but had no effect on rad2
. These findings suggest that
aberrant replication caused by allele-specific mutations of these
replication proteins can accumulate potentially mutagenic DNA
structures. The checkpoint Rad-mediated pathways monitor and signal the
aberrant replication in both the deletion and duplication mutators,
while Cds1 mediates recovery from aberrant replication and prevents formation of deletion mutations specifically in the thermosensitive deletion replication mutators.
*
Corresponding author. Mailing address: Department of
Pathology, Stanford University School of Medicine, Stanford, California 94305-5324. Phone: (650) 725-4907. Fax: (650) 725-6902. E-mail: twang{at}cmgm.stanford.edu.
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