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Yet, the precise mechanisms of how LRRC8A and LRRC8D mediate this function are largely unknown. Here, we identify NAA60, an N-terminal acetyltransferase, which localizes to the Golgi apparatus to affect LRRC8A and LRRC8D function. Our data suggest that NAA60 acetylates the LRRC8A\/D N-termini, and its loss decreases cis- and carboplatin uptake resulting in drug resistance of otherwise hypersensitive BRCA1;p53-deficient cells and tumors. Furthermore, we mimicked the absence of the neutralizing acetyl moiety that is observed after loss of NAA60 by introducing positively charged amino acids at the N-termini of LRRC8A\/D, which indeed decreased cis- and carboplatin sensitivity. Our findings highlight the importance of N-terminal acetylation by NAA60 for effective platinum drug uptake, offering new insights into overcoming drug resistance.<\/jats:p>","DOI":"10.1038\/s42003-025-08826-x","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T12:51:23Z","timestamp":1759755083000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["NAA60 facilitates LRRC8A- and LRRC8D-mediated platinum drug uptake"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7030-4550","authenticated-orcid":false,"given":"Carmen Alexandra","family":"Widmer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Moyseos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismar","family":"Klebic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Dettwiler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8308-5493","authenticated-orcid":false,"given":"Mart\u00edn","family":"Gonz\u00e1lez-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Gogola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Siffert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Buchs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Braga-Lagache","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Christine","family":"Uldry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9264-9792","authenticated-orcid":false,"given":"Jos","family":"Jonkers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6364-7325","authenticated-orcid":false,"given":"Manfred","family":"Heller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2044-9844","authenticated-orcid":false,"given":"Sven","family":"Rottenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,6]]},"reference":[{"key":"8826_CR1","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.4161\/epi.22561","volume":"7","author":"OA Stefansson","year":"2012","unstructured":"Stefansson, O. 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