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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\u2014a molecular fingerprint of 8-oxoguanine overproduction. Mechanistically, these lesions are exacerbated by error-prone DNA polymerase \u03b6 but mitigated by the concerted actions of Ogg1-mediated excision and DNA polymerase \u03b7. 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.<\/jats:p>","DOI":"10.1371\/journal.pgen.1012326","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:46:35Z","timestamp":1791222395000},"page":"e1012326","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoupling metabolic defense: Mutational and recombinational chaos in Sod1-deficient cells"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7285-8733","authenticated-orcid":true,"given":"Yang","family":"Sui","sequence":"first","affiliation":[{"name":"Zhejiang University","place":["Zhoushan, China"],"department":["National Key Laboratory of Biobased Transportation Fuel Technology, Ocean College"]},{"name":"Zhejiang University","place":["Sanya, China"],"department":["Hainan 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