A genomewide screen of a collection of 4,847 yeast gene deletion mutants was carried out to identify the genes required for suppressing mutations in the CAN1 forward-mutation assay. The primary screens and subsequent analysis allowed (i) identification of 18 known mutator mutants, providing a solid means for checking the efficiency of the screen, and (ii) identification of a number of genes not known previously to be involved in suppressing mutations. Among the previously uncharacterized mutation-suppressing genes were six genes of unknown function including four (CSM2, SHU2, SHU1, and YLR376c) encoding proteins that interact with each other and promote resistance to killing by methyl methanesulfonate, one gene (EGL1) previously identified as suppressing Ty1 mobility and recombination between repeated sequences, and one gene (YLR154c) that was not associated with any known processes. In addition, five genes (TSA1, SOD1, LYS7, SKN7, and YAP1) implicated in the oxidative-stress responses were found to play a significant role in mutation suppression. Furthermore, TSA1, which encodes thioredoxin peroxidase, was found to strongly suppress gross chromosomal rearrangements. These results provide a global view of the nonessential genes involved in preventing mutagenesis. Study of such genes should provide useful clues in identification of human genes potentially involved in cancer predisposition and in understanding their mechanisms of action. Maintaining the stability of the genome is critical to cell survival and normal cell growth. Inherited or acquired deficiencies in genome maintenance systems contribute significantly to the onset of cancer as evidenced by the observation that a number of the DNA-repair and checkpoint genes are mutated in cancer susceptibility syndromes and sporadic cancers (1-4). This raises the possibility that other genetic defects causing genome instability and mutator phenotypes could contribute to carcinogenesis. The yeast Saccharomyces cerevisiae provides an ideal system for the analysis of mutator phenotypes. Such mutator phenotypes are expected to result from defects in genes with products that act to maintain genome stability. Knowledge obtained from S. cerevisiae about specific DNA-sequence changes, the rates at which they arise, and the influence of different genes and alleles on these changes has yielded insights into the processes that ensure genomic stability. One example in this regard concerns the relationship between DNA mismatch repair (MMR) defects and microsatellite sequence instability (5-7). Mutations in different components of the MMR system can differentially affect the repair of replication errors, and individual MMR-defective mutants display distinct mutation spectra including increased accumulation of frameshift mutations in simple repeat sequences (5-7). In fact, the link between microsatellite sequence instability and MMR defects first demonstrated in Escherichia coli and yeast provided a critical clue in the identification of MMR defects in the cancer-predisposition s...
Background: The t(12;21)(p13;q22) translocation is found in 20 to 25% of cases of childhood Blineage acute lymphoblastic leukemia (B-ALL). This rearrangement results in the fusion of ETV6 (TEL) and RUNX1 (AML1) genes and defines a relatively uniform category, although only some patients suffer very late relapse. TEL/AML1-positive patients are thus an interesting subgroup to study, and such studies should elucidate the biological processes underlying TEL/AML1 pathogenesis. We report an analysis of gene expression in 60 children with B-lineage ALL using Agilent whole genome oligo-chips (44K-G4112A) and/or real time RT-PCR.
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