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Using lentiviral constructs, we investigated whether cancer\u2010related RAD50 missense variants can complement the delayed damage response after exposure to the chemotherapeutic agent epirubicin and\/or mitotic progression in RAD50\u2010deficient fibroblasts. Eight missense variants, all capable of forming an MRN complex, supported the DNA damage response and mitotic features to different extents, indicating these functions are separable. Three variants showed both an impaired epirubicin response and slowed cell division in the likely pathogenic range. Assessing RAD50 missense variants with distinct functional readouts may help to further elucidate their differential roles in immunodeficiency and cancer and could improve therapeutic strategies.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"box\" position=\"anchor\">\n                      <jats:caption>\n                        <jats:title>Impact statement<\/jats:title>\n                      <\/jats:caption>\n                      <jats:p>RAD50 has a strong impact on DNA repair and cancer therapy. Here, we analyse RAD50 missense variants at four functional levels. Some variants showed an impaired epirubicin response and mitotic progression in the pathological range, while for others these endpoints were separable. Functional heterogeneity of RAD50 variants could contribute to clinical variability.<\/jats:p>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1002\/1873-3468.70175","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T11:54:08Z","timestamp":1759319648000},"page":"3656-3668","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>RAD50<\/scp>\n                    missense variants differentially affect the\n                    <scp>DNA<\/scp>\n                    damage response and mitotic progression"],"prefix":"10.1002","volume":"599","author":[{"given":"Hanna","family":"Redeker","sequence":"first","affiliation":[{"name":"Gynaecology Research Unit Hannover Medical School  Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Swantje","family":"Kebel","sequence":"additional","affiliation":[{"name":"Gynaecology Research Unit 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