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Hence, targeting DNA damage therapeutically may counteract age\u2010related cellular dysfunction and disease, such as neurodegenerative conditions and cancer. Identifying novel DNA repair mechanisms therefore reveals new therapeutic interventions for multiple human diseases. In neurons, non\u2010homologous end\u2010joining (NHEJ) is the only mechanism available to repair double\u2010stranded DNA breaks (DSB), which is much more error prone than other DNA repair processes. However, there are no therapeutic interventions to enhance DNA repair in diseases affecting neurons. NHEJ is also a useful target for DNA repair\u2010based cancer therapies to selectively kill tumour cells. Protein disulphide isomerase (PDI) participates in many diseases, but its roles in these conditions remain poorly defined. PDI exhibits both chaperone and redox\u2010dependent oxidoreductase activity, and while primarily localised in the endoplasmic reticulum it has also been detected in other cellular locations. We describe here a novel role for PDI in DSB repair following at least two types of DNA damage. PDI functions in NHEJ, and following DNA damage, it relocates to the nucleus, where it co\u2010localises with critical DSB repair proteins at DNA damage foci. A redox\u2010inactive mutant of PDI lacking its two active site cysteine residues was not protective, however. Hence, the redox activity of PDI mediates DNA repair, highlighting these cysteines as targets for therapeutic intervention. The therapeutic potential of PDI was also confirmed by its protective activity in a whole organism against DNA damage induced in\u00a0vivo in zebrafish. Hence, harnessing the redox function of PDI has potential as a novel therapeutic target against DSB DNA damage relevant to several human diseases.<\/jats:p>","DOI":"10.1111\/acel.70079","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T05:15:14Z","timestamp":1747286114000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Redox Activity of Protein Disulphide Isomerase Functions in Non\u2010Homologous End\u2010Joining Repair to Prevent\n                    <scp>DNA<\/scp>\n                    Damage"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7626-1096","authenticated-orcid":false,"given":"Sina","family":"Shadfar","sequence":"first","affiliation":[{"name":"Motor Neuron Disease Research Centre, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New\u00a0South Wales 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