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  • 1
    Online Resource
    Online Resource
    Changes in metabolic landscapes shape divergent but distinct mutational signatures and cytotoxic consequences of redox stress
    Oxford University Press (OUP) ; 2023
    In:  Nucleic Acids Research Vol. 51, No. 10 ( 2023-06-09), p. 5056-5072
    Details
    In: Nucleic Acids Research, Oxford University Press (OUP), Vol. 51, No. 10 ( 2023-06-09), p. 5056-5072
    Abstract: Mutational signatures discerned in cancer genomes, in aging tissues and in cells exposed to toxic agents, reflect complex processes underlying transformation of cells from normal to dysfunctional. Due to its ubiquitous and chronic nature, redox stress contributions to cellular makeover remain equivocal. The deciphering of a new mutational signature of an environmentally-relevant oxidizing agent, potassium bromate, in yeast single strand DNA uncovered a surprising heterogeneity in the mutational signatures of oxidizing agents. NMR-based analysis of molecular outcomes of redox stress revealed profound dissimilarities in metabolic landscapes following exposure to hydrogen peroxide versus potassium bromate. The predominance of G to T substitutions in the mutational spectra distinguished potassium bromate from hydrogen peroxide and paraquat and mirrored the observed metabolic changes. We attributed these changes to the generation of uncommon oxidizing species in a reaction with thiol-containing antioxidants; a nearly total depletion of intracellular glutathione and a paradoxical augmentation of potassium bromate mutagenicity and toxicity by antioxidants. Our study provides the framework for understanding multidimensional processes triggered by agents collectively known as oxidants. Detection of increased mutational loads associated with potassium bromate-related mutational motifs in human tumors may be clinically relevant as a biomarker of this distinct type of redox stress.
    Type of Medium: Online Resource
    ISSN: 0305-1048 , 1362-4962
    URL: Article
    DOI: 10.1093/nar/gkad305
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1472175-2
    SSG: 12
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  • 2
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    Online Resource
    The Sister Chromatid Cohesion Pathway Suppresses Multiple Chromosome Gain and Chromosome Amplification
    Oxford University Press (OUP) ; 2014
    In:  Genetics Vol. 196, No. 2 ( 2014-02-01), p. 373-384
    Details
    In: Genetics, Oxford University Press (OUP), Vol. 196, No. 2 ( 2014-02-01), p. 373-384
    Abstract: Gain or loss of chromosomes resulting in aneuploidy can be important factors in cancer and adaptive evolution. Although chromosome gain is a frequent event in eukaryotes, there is limited information on its genetic control. Here we measured the rates of chromosome gain in wild-type yeast and sister chromatid cohesion (SCC) compromised strains. SCC tethers the newly replicated chromatids until anaphase via the cohesin complex. Chromosome gain was measured by selecting and characterizing copper-resistant colonies that emerged due to increased copies of the metallothionein gene CUP1. Although all defective SCC diploid strains exhibited increased rates of chromosome gain, there were 15-fold differences between them. Of all mutants examined, a hypomorphic mutation at the cohesin complex caused the highest rate of chromosome gain while disruption of WPL1, an important regulator of SCC and chromosome condensation, resulted in the smallest increase in chromosome gain. In addition to defects in SCC, yeast cell type contributed significantly to chromosome gain, with the greatest rates observed for homozygous mating-type diploids, followed by heterozygous mating type, and smallest in haploids. In fact, wpl1-deficient haploids did not show any difference in chromosome gain rates compared to wild-type haploids. Genomic analysis of copper-resistant colonies revealed that the “driver” chromosome for which selection was applied could be amplified to over five copies per diploid cell. In addition, an increase in the expected driver chromosome was often accompanied by a gain of a small number of other chromosomes. We suggest that while chromosome gain due to SCC malfunction can have negative effects through gene imbalance, it could also facilitate opportunities for adaptive changes. In multicellular organisms, both factors could lead to somatic diseases including cancer.
    Type of Medium: Online Resource
    ISSN: 1943-2631
    URL: Article
    DOI: 10.1534/genetics.113.159202
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2014
    detail.hit.zdb_id: 1477228-0
    SSG: 12
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  • 3
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    Online Resource
    Mutation signatures specific to DNA alkylating agents in yeast and cancers
    Oxford University Press (OUP) ; 2020
    In:  Nucleic Acids Research Vol. 48, No. 7 ( 2020-04-17), p. 3692-3707
    Details
    In: Nucleic Acids Research, Oxford University Press (OUP), Vol. 48, No. 7 ( 2020-04-17), p. 3692-3707
    Abstract: Alkylation is one of the most ubiquitous forms of DNA lesions. However, the motif preferences and substrates for the activity of the major types of alkylating agents defined by their nucleophilic substitution reactions (SN1 and SN2) are still unclear. Utilizing yeast strains engineered for large-scale production of single-stranded DNA (ssDNA), we probed the substrate specificity, mutation spectra and signatures associated with DNA alkylating agents. We determined that SN1-type agents preferably mutagenize double-stranded DNA (dsDNA), and the mutation signature characteristic of the activity of SN1-type agents was conserved across yeast, mice and human cancers. Conversely, SN2-type agents preferably mutagenize ssDNA in yeast. Moreover, the spectra and signatures derived from yeast were detectable in lung cancers, head and neck cancers and tumors from patients exposed to SN2-type alkylating chemicals. The estimates of mutation loads associated with the SN2-type alkylation signature were higher in lung tumors from smokers than never-smokers, pointing toward the mutagenic activity of the SN2-type alkylating carcinogens in cigarettes. In summary, our analysis of mutations in yeast strains treated with alkylating agents, as well as in whole-exome and whole-genome-sequenced tumors identified signatures highly specific to alkylation mutagenesis and indicate the pervasive nature of alkylation-induced mutagenesis in cancers.
    Type of Medium: Online Resource
    ISSN: 0305-1048 , 1362-4962
    URL: Article
    DOI: 10.1093/nar/gkaa150
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1472175-2
    SSG: 12
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  • 4
    Online Resource
    Online Resource
    Genetic Factors Affecting the Impact of DNA Polymerase ∂ Proofreading Activity on Mutation Avoidance in Yeast
    Oxford University Press (OUP) ; 1999
    In:  Genetics Vol. 152, No. 1 ( 1999-05-01), p. 47-59
    Details
    In: Genetics, Oxford University Press (OUP), Vol. 152, No. 1 ( 1999-05-01), p. 47-59
    Abstract: Base selectivity, proofreading, and postreplication mismatch repair are important for replication fidelity. Because proofreading plays an important role in error correction, we have investigated factors that influence its impact in the yeast Saccharomyces cerevisiae. We have utilized a sensitive mutation detection system based on homonucleotide runs of 4 to 14 bases to examine the impact of DNA polymerase ∂ proofreading on mutation avoidance. The contribution of DNA polymerase ∂ proofreading on error avoidance was found to be similar to that of DNA polymerase ε proofreading in short homonucleotide runs (A4 and A5) but much greater than the contribution of DNA polymerase ε proofreading in longer runs. We have identified an intraprotein interaction affecting mutation prevention that results from mutations in the replication and the proofreading regions, resulting in an antimutator phenotype relative to a proofreading defect. Finally, a diploid strain with a defect in DNA polymerase ∂ proofreading exhibits a higher mutation rate than a haploid strain. We suggest that in the diploid population of proofreading defective cells there exists a transiently hypermutable fraction that would be inviable if cells were haploids.
    Type of Medium: Online Resource
    ISSN: 1943-2631
    URL: Article
    DOI: 10.1093/genetics/152.1.47
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 1999
    detail.hit.zdb_id: 1477228-0
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  • 5
    Online Resource
    Online Resource
    The Prevention of Repeat-Associated Deletions in Saccharomyces cerevisiae by Mismatch Repair Depends on Size and Origin of Deletions
    Oxford University Press (OUP) ; 1996
    In:  Genetics Vol. 143, No. 4 ( 1996-08-01), p. 1579-1587
    Details
    In: Genetics, Oxford University Press (OUP), Vol. 143, No. 4 ( 1996-08-01), p. 1579-1587
    Abstract: We have investigated the effects of mismatch repair on 1- to 61-bp deletions in the yeast Saccharomyces cerevisiae. The deletions are likely to involve unpaired loop intermediates resulting from DNA polymerase slippage. The mutator effects of mutations in the DNA polymerase δ (POL3) gene and the recombinational repair RAD52 gene were studied in combination with mismatch repair defects. The pol3-t mutation increased up to 1000-fold the rate of extended (7-61 bp) but not of 1-bp deletions. In a rad52 null mutant only the 1-bp deletions were increased (12-fold). The mismatch repair mutations pmsl, msh2 and msh3 did not affect 31- and 61-bp deletions in the pol3-t but increased the rates of 7- and 1-bp deletions. We propose that loops less than or equal to seven bases generated during replication are subject to mismatch repair by the PMSI, MSH2, MSH3 system and that it cannot act on loops ≤31 bases. In contrast to the pol3-t, the enhancement of 1-bp deletions in a rad52 mutant is not altered by a pmsl mutation. Thus, mismatch repair appears to be specific to errors of DNA synthesis generated during semiconservative replication.
    Type of Medium: Online Resource
    ISSN: 1943-2631
    URL: Article
    DOI: 10.1093/genetics/143.4.1579
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 1996
    detail.hit.zdb_id: 1477228-0
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  • 6
    Online Resource
    Online Resource
    Factors Affecting Inverted Repeat Stimulation of Recombination and Deletion in Saccharomyces cerevisiae
    Oxford University Press (OUP) ; 1998
    In:  Genetics Vol. 148, No. 4 ( 1998-04-01), p. 1507-1524
    Details
    In: Genetics, Oxford University Press (OUP), Vol. 148, No. 4 ( 1998-04-01), p. 1507-1524
    Abstract: Inverted DNA repeats are an at-risk motif for genetic instability that can induce both deletions and recombination in yeast. We investigated the role of the length of inverted repeats and size of the DNA separating the repeats for deletion and recombination. Stimulation of both deletion and recombination was directly related to the size of inverted repeats and inversely related to the size of intervening spacers. A perfect palindrome, formed by two 1.0-kb URA3-inverted repeats, increased intra- and interchromosomal recombination in the adjacent region 2,400-fold and 17,000-fold, respectively. The presence of a strong origin of replication in the spacer reduced both rates of deletion and recombination. These results support a model in which the stimulation of deletion and recombination by inverted repeats is initiated by a secondary structure formed between single-stranded DNA of inverted repeats during replication.
    Type of Medium: Online Resource
    ISSN: 1943-2631
    URL: Article
    DOI: 10.1093/genetics/148.4.1507
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 1998
    detail.hit.zdb_id: 1477228-0
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  • 7
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    Online Resource
    Apn1 and Apn2 endonucleases prevent accumulation of repair-associated DNA breaks in budding yeast as revealed by direct chromosomal analysis
    Oxford University Press (OUP) ; 2008
    In:  Nucleic Acids Research Vol. 36, No. 6 ( 2008-4), p. 1836-1846
    Details
    In: Nucleic Acids Research, Oxford University Press (OUP), Vol. 36, No. 6 ( 2008-4), p. 1836-1846
    Type of Medium: Online Resource
    ISSN: 1362-4962 , 0305-1048
    URL: Article
    DOI: 10.1093/nar/gkm1148
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2008
    detail.hit.zdb_id: 1472175-2
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  • 8
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    Online Resource
    Glycidamide-induced hypermutation in yeast single-stranded DNA reveals a ubiquitous clock-like mutational motif in humans
    Oxford University Press (OUP) ; 2023
    In:  Nucleic Acids Research Vol. 51, No. 17 ( 2023-09-22), p. 9075-9100
    Details
    In: Nucleic Acids Research, Oxford University Press (OUP), Vol. 51, No. 17 ( 2023-09-22), p. 9075-9100
    Abstract: Mutagens often prefer specific nucleotides or oligonucleotide motifs that can be revealed by studying the hypermutation spectra in single-stranded (ss) DNA. We utilized a yeast model to explore mutagenesis by glycidamide, a simple epoxide formed endogenously in humans from the environmental toxicant acrylamide. Glycidamide caused ssDNA hypermutation in yeast predominantly in cytosines and adenines. The most frequent mutations in adenines occurred in the nAt→nGt trinucleotide motif. Base substitutions A→G in this motif relied on Rev1 translesion polymerase activity. Inactivating Rev1 did not alter the nAt trinucleotide preference, suggesting it may be an intrinsic specificity of the chemical reaction between glycidamide and adenine in the ssDNA. We found this mutational motif enriched in published sequencing data from glycidamide-treated mouse cells and ubiquitous in human cancers. In cancers, this motif was positively correlated with the single base substitution (SBS) smoking-associated SBS4 signature, with the clock-like signatures SBS1, SBS5, and was strongly correlated with smoking history and with age of tumor donors. Clock-like feature of the motif was also revealed in cells of human skin and brain. Given its pervasiveness, we propose that this mutational motif reflects mutagenic lesions to adenines in ssDNA from a potentially broad range of endogenous and exogenous agents.
    Type of Medium: Online Resource
    ISSN: 0305-1048 , 1362-4962
    URL: Article
    DOI: 10.1093/nar/gkad611
    RVK:
    WA 15000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1472175-2
    SSG: 12
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  • 9
    Online Resource
    Online Resource
    Tracing Lung Cancer Risk Factors Through Mutational Signatures in Never-Smokers
    Oxford University Press (OUP) ; 2021
    In:  American Journal of Epidemiology Vol. 190, No. 6 ( 2021-06-01), p. 962-976
    Details
    In: American Journal of Epidemiology, Oxford University Press (OUP), Vol. 190, No. 6 ( 2021-06-01), p. 962-976
    Abstract: Epidemiologic studies often rely on questionnaire data, exposure measurement tools, and/or biomarkers to identify risk factors and the underlying carcinogenic processes. An emerging and promising complementary approach to investigate cancer etiology is the study of somatic “mutational signatures” that endogenous and exogenous processes imprint on the cellular genome. These signatures can be identified from a complex web of somatic mutations thanks to advances in DNA sequencing technology and analytical algorithms. This approach is at the core of the Sherlock-Lung study (2018–ongoing), a retrospective case-only study of over 2,000 lung cancers in never-smokers (LCINS), using different patterns of mutations observed within LCINS tumors to trace back possible exposures or endogenous processes. Whole genome and transcriptome sequencing, genome-wide methylation, microbiome, and other analyses are integrated with data from histological and radiological imaging, lifestyle, demographic characteristics, environmental and occupational exposures, and medical records to classify LCINS into subtypes that could reveal distinct risk factors. To date, we have received samples and data from 1,370 LCINS cases from 17 study sites worldwide and whole-genome sequencing has been completed on 1,257 samples. Here, we present the Sherlock-Lung study design and analytical strategy, also illustrating some empirical challenges and the potential for this approach in future epidemiologic studies.
    Type of Medium: Online Resource
    ISSN: 0002-9262 , 1476-6256
    URL: Article
    DOI: 10.1093/aje/kwaa234
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2030043-8
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