期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 99, 期 21, 页码 13669-13674出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.202242599
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资金
- NCI NIH HHS [CA 90911, R01 CA090911] Funding Source: Medline
- NHLBI NIH HHS [5T32 HL 07157] Funding Source: Medline
When a replication fork collides with a DNA topoisomerase 1 (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.
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