Reference: Hoskins J and Butler JS (2008) RNA-Based 5-Fluorouracil Toxicity Requires the Pseudouridylation Activity of Cbf5p. Genetics 179(1):323-30

Reference Help

Abstract

The chemotherapeutic drug 5-fluorouracil (5FU) disrupts DNA synthesis by inhibiting the enzymatic conversion of dUMP to dTMP. However, mounting evidence indicates that 5FU has important effects on RNA metabolism that contribute significantly to the toxicity of the drug. Strains with mutations in nuclear RNA-processing exosome components, including Rrp6p, exhibit strong 5FU hypersensitivity. Studies also suggest that 5FU-containing RNA can inhibit pseudouridylation, the most abundant post-transcriptional modification of noncoding RNA. We examined the effect of modulating the expression and activity of the essential yeast rRNA pseudouridylase Cbf5p on the 5FU hypersensitivity of an rrp6-Delta mutant strain. Depletion of Cbf5p suppressed the 5FU hypersensitivity of an rrp6-Delta strain, while high-copy expression enhanced sensitivity to the drug. A mutation in the catalytic site of Cbf5p also suppressed the 5FU hypersensitivity in the rrp6-Delta mutant, suggesting that RNA-based 5FU toxicity requires the pseudouridylation activity of Cbf5p. High-copy expression of box H/ACA snoRNAs also suppressed the 5FU hypersensitivity of an rrp6-Delta strain, suggesting that sequestration of Cbf5p to a particular guide RNA reduces Cbf5p-dependent 5FU toxicity. On the basis of these results and previous reports that certain pseudouridylases form stable adducts with 5FU-containing RNA, we suggest that Cbf5p binds tightly to substrates containing 5FU, causing their degradation by the TRAMP/exosome-mediated RNA surveillance pathway.

Reference Type
Journal Article
Authors
Hoskins J, Butler JS
Primary Lit For
Additional Lit For
Review For

Interaction Annotations

Increase the total number of rows showing on this page by using the pull-down located below the table, or use the page scroll at the table's top right to browse through the table's pages; use the arrows to the right of a column header to sort by that column; filter the table using the "Filter" box at the top of the table; click on the small "i" buttons located within a cell for an annotation to view further details about experiment type and any other genes involved in the interaction.

Interactor Interactor Type Assay Annotation Action Modification Phenotype Source Reference

Gene Ontology Annotations

Increase the total number of rows showing on this page using the pull-down located below the table, or use the page scroll at the table's top right to browse through the table's pages; use the arrows to the right of a column header to sort by that column; filter the table using the "Filter" box at the top of the table.

Gene Gene Ontology Term Qualifier Aspect Method Evidence Source Assigned On Annotation Extension Reference

Phenotype Annotations

Increase the total number of rows showing on this page using the pull-down located below the table, or use the page scroll at the table's top right to browse through the table's pages; use the arrows to the right of a column header to sort by that column; filter the table using the "Filter" box at the top of the table; click on the small "i" buttons located within a cell for an annotation to view further details.

Gene Phenotype Experiment Type Mutant Information Strain Background Chemical Details Reference

Regulation Annotations

Increase the total number of rows displayed on this page using the pull-down located below the table, or use the page scroll at the table's top right to browse through the table's pages; use the arrows to the right of a column header to sort by that column; to filter the table by a specific experiment type, type a keyword into the Filter box (for example, “microarray”); download this table as a .txt file using the Download button or click Analyze to further view and analyze the list of target genes using GO Term Finder, GO Slim Mapper, SPELL, or YeastMine.

Regulator Target Experiment Assay Construct Conditions Strain Background Reference