Yeast Tdp1 and Rad1-Rad10 function as redundant pathways for repairing Top1 replicative damage.

When a replication fork collides with a DNA topoisomerase I (Top1) cleavage complex, the covalently bound enzyme must be removed from the DNA 3' end before recombination-dependent replication restart. Here we report that the tyrosyl-DNA phosphodiesterase Tdp1 and the structure-specific endonuclease Rad1-Rad10 function as primary alternative pathways of Top1 repair ...
in Saccharomyces cerevisiae. Thus, tdp1 rad1 cells (including the catalytic point mutant rad1-D869A) not only are highly sensitive to the Top1 poison camptothecin but also exhibit a TOP1-dependent growth delay. Extensive genetic analysis revealed that both Tdp1 and Rad1-Rad10 repair proceed through recombination that equally depends on RAD52, RAD51, and RAD50. The Rad1-Rad10 pathway further particularly depends on RAD59 and SRS2 but is independent of other nucleotide excision repair genes. Although this pattern is consistent with Rad1-Rad10 removing Top1 in a manner similar to its removal of nonhomologous tails during gene conversion, these differ in that Top1 removal does not require Msh2-Msh3. Finally, we show that yeast lacking the Rad1-Rad10-related proteins Mus81-Mms4 display a unique pattern of camptothecin sensitivity and suggest a concerted model for the action of these endonucleases.
Mesh Terms:
Camptothecin, DNA Damage, DNA Repair, DNA Repair Enzymes, DNA Replication, DNA Topoisomerases, Type I, DNA, Fungal, DNA-Binding Proteins, Endonucleases, Enzyme Inhibitors, Flap Endonucleases, Fungal Proteins, Genes, Fungal, Models, Biological, Mutation, Oligonucleotide Array Sequence Analysis, Phosphoric Diester Hydrolases, Recombination, Genetic, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Single-Strand Specific DNA and RNA Endonucleases, Trans-Activators
Proc. Natl. Acad. Sci. U.S.A.
Date: Oct. 15, 2002
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