دورية أكاديمية
Complex mutation profiles in mismatch repair and ribonucleotide reductase mutants reveal novel repair substrate specificity of MutS homolog (MSH) complexes.
| العنوان: | Complex mutation profiles in mismatch repair and ribonucleotide reductase mutants reveal novel repair substrate specificity of MutS homolog (MSH) complexes. |
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| المؤلفون: | Lamb NA; Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA., Bard JE; Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA.; University at Buffalo Genomics and Bioinformatics Core, State University of New York at Buffalo, Buffalo, NY 14203, USA., Loll-Krippleber R; Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada., Brown GW; Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada., Surtees JA; Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA.; Genetics, Genomics and Bioinformatics Graduate Program, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY 14203, USA. |
| المصدر: | Genetics [Genetics] 2022 Jul 30; Vol. 221 (4). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: United States NLM ID: 0374636 Publication Model: Print Cited Medium: Internet ISSN: 1943-2631 (Electronic) Linking ISSN: 00166731 NLM ISO Abbreviation: Genetics Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [Oxford] : Oxford University Press Original Publication: Austin, Tex. [etc.] |
| مواضيع طبية MeSH: | Ribonucleotide Reductases*/genetics , Ribonucleotide Reductases*/metabolism , Saccharomyces cerevisiae Proteins*/genetics, Humans ; Deoxyribonucleosides ; DNA Mismatch Repair ; DNA Repair ; DNA-Binding Proteins/metabolism ; Mutation ; MutS Homolog 2 Protein/genetics ; MutS Homolog 2 Protein/metabolism ; MutS Proteins/genetics ; MutS Proteins/metabolism ; Substrate Specificity |
| مستخلص: | Determining mutation signatures is standard for understanding the etiology of human tumors and informing cancer treatment. Multiple determinants of DNA replication fidelity prevent mutagenesis that leads to carcinogenesis, including the regulation of free deoxyribonucleoside triphosphate pools by ribonucleotide reductase and repair of replication errors by the mismatch repair system. We identified genetic interactions between rnr1 alleles that skew and/or elevate deoxyribonucleoside triphosphate levels and mismatch repair gene deletions. These defects indicate that the rnr1 alleles lead to increased mutation loads that are normally acted upon by mismatch repair. We then utilized a targeted deep-sequencing approach to determine mutational profiles associated with mismatch repair pathway defects. By combining rnr1 and msh mutations to alter and/or increase deoxyribonucleoside triphosphate levels and alter the mutational load, we uncovered previously unreported specificities of Msh2-Msh3 and Msh2-Msh6. Msh2-Msh3 is uniquely able to direct the repair of G/C single-base deletions in GC runs, while Msh2-Msh6 specifically directs the repair of substitutions that occur at G/C dinucleotides. We also identified broader sequence contexts that influence variant profiles in different genetic backgrounds. Finally, we observed that the mutation profiles in double mutants were not necessarily an additive relationship of mutation profiles in single mutants. Our results have implications for interpreting mutation signatures from human tumors, particularly when mismatch repair is defective. (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.) |
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| فهرسة مساهمة: | Keywords: dNTP pools; deep sequencing; mismatch repair; mutation profiles; replication fidelity; ribonucleotide reductase |
| المشرفين على المادة: | 0 (Deoxyribonucleosides) 0 (DNA-Binding Proteins) EC 3.6.1.3 (MutS Homolog 2 Protein) EC 3.6.1.3 (MutS Proteins) EC 1.17.4.- (Ribonucleotide Reductases) 0 (Saccharomyces cerevisiae Proteins) |
| تواريخ الأحداث: | Date Created: 20220610 Date Completed: 20221229 Latest Revision: 20230611 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC9339293 |
| DOI: | 10.1093/genetics/iyac092 |
| PMID: | 35686905 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1943-2631 |
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| DOI: | 10.1093/genetics/iyac092 |