{
  "abstract": "Superoxide dismutase 1 (Sod1) is long recognized as a frontline antioxidant, yet its broader role in safeguarding the eukaryotic genome remains under-explored. Here, using a yeast model, we reveal that Sod1 is an indispensable guardian of genomic integrity. Its absence unleashes a genomic storm: whole-genome sequencing uncovered a dramatic surge in single nucleotide variations (13-fold), loss of heterozygosity (12-fold), chromosomal rearrangements (4-fold), and a staggering 48-fold increase in aneuploidy. Remarkably, this genomic instability was completely abolished under anaerobic conditions, identifying reactive oxygen species as the sole executioner. We demonstrate that Sod1 deficiency sculpts a unique mutational landscape dominated by C:G to A:T transversions—a molecular fingerprint of 8-oxoguanine overproduction. Mechanistically, these lesions are exacerbated by error-prone DNA polymerase ζ but mitigated by the concerted actions of Ogg1-mediated excision and DNA polymerase η. Critically, we show that Amyotrophic Lateral Sclerosis-associated variants are not created equal: the H48Q mutation shatters genome stability, whereas others (A4V, G36R, and G93A) remain benign in this context. Unlike yeast Sod1, human Sod1 is highly resistant to amino acid substitutions outside copper-binding sites, thus preventing the loss of enzyme function. Overall, our findings provide a mechanistically framework for understanding how Sod1 dysfunction drives genome instability in eukaryotic cells. Author summary: Sod1 is a primary antioxidant defense enzyme, yet its comprehensive role in preserving eukaryotic genome stability remains insufficiently mapped. Using a diploid yeast model, we demonstrate that Sod1 loss triggers global genomic chaos. Anaerobic growth and antioxidative agent abolish this instability, confirming reactive oxygen species as the sole genotoxic driver. Mechanistically, Sod1 deficiency drives a distinct mutational spectrum dominated by C:G to A:T transversions resulting from 8-oxoguanine accumulation. While the error-prone DNA polymerase zeta (Rev3) promotes these mutations, Ogg1-mediated base excision repair and DNA polymerase eta (Rad30) actively suppress them. Crucially, evaluation of clinical Amyotrophic Lateral Sclerosis (ALS)-associated SOD1 mutations reveals functional heterogeneity: the metal-binding H48Q variant severely shatters genome stability, whereas variants such as A4V, G36R, and G93A remain benign in this context. Overall, this study establishes a high-resolution framework illustrating how antioxidant loss drives global genome instability and provides mechanistic insights into Sod1-linked human pathologies.",
  "abstract_shown": true,
  "affiliations": [
    "National Key Laboratory of Biobased Transportation Fuel Technology, Ocean College, Zhejiang University, Zhoushan, China",
    "Hainan Institute, Zhejiang University, Sanya, China",
    "College of Life Sciences, Zhejiang University, Hangzhou, China"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yang Sui"
    },
    {
      "affs": [
        1
      ],
      "name": "Dao-Qiong Zheng"
    },
    {
      "affs": [
        2
      ],
      "name": "Yeke Wang"
    },
    {
      "name": "Shan-Shan Zhao"
    },
    {
      "name": "Ke-Jing Li"
    },
    {
      "name": "Cunqi Ye"
    },
    {
      "name": "Ke Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/09ggnan1sq8sy.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pgen.1012326",
  "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012326",
  "id": "09ggnan1sq8sy",
  "issns": [
    "1553-7404"
  ],
  "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012326",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|DNA Repair Mechanisms"
    ],
    [
      "plos",
      "/Biology and life sciences/Biochemistry/Nucleic acids/DNA/DNA replication"
    ],
    [
      "plos",
      "/Biology and life sciences/Cell biology/Oxidative stress"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/DNA/DNA replication"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Genomics"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Mutation/Point mutation"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Mutation/Substitution mutation"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Eukaryota/Fungi/Yeast"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Eukaryota/Fungi/Yeast/Saccharomyces/Saccharomyces cerevisiae"
    ],
    [
      "plos",
      "/Research and analysis methods/Animal studies/Experimental organism systems/Model organisms/Saccharomyces cerevisiae"
    ],
    [
      "plos",
      "/Research and analysis methods/Animal studies/Experimental organism systems/Yeast and fungal models"
    ],
    [
      "plos",
      "/Research and analysis methods/Animal studies/Experimental organism systems/Yeast and fungal models/Saccharomyces cerevisiae"
    ],
    [
      "plos",
      "/Research and analysis methods/Model organisms/Saccharomyces cerevisiae"
    ]
  ],
  "openalex": "W7220417744",
  "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012326&type=printable",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-05",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/09ggnan1sq8sy.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:37Z",
      "native_id": "10.1371/journal.pgen.1012326",
      "source": "plos",
      "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012326"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "plos:genetics",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Decoupling metabolic defense: Mutational and recombinational chaos in Sod1-deficient cells",
  "title_text": "Decoupling metabolic defense: Mutational and recombinational chaos in Sod1-deficient cells",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:37Z",
  "url": "https://research.draconitic.com/paper/09ggnan1sq8sy",
  "venue": "PLOS Genetics",
  "versions": []
}