NAA60 facilitates LRRC8A- and LRRC8D-mediated platinum drug uptake

The platinum-based drugs cis- and carboplatin, which are crucial for treating cancers with DNA repair defects, like those caused by BRCA1/2 mutations, rely on the volume-regulated anion channel subunits LRRC8A and LRRC8D for about 50% of cellular drug uptake. Yet, the precise mechanisms of how LRRC8...

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Vydáno v:	Communications biology Ročník 8; číslo 1; s. 1431 - 18
Hlavní autoři:	Widmer, Carmen Alexandra, Moyseos, Anna, Klebic, Ismar, Dettwiler, Martina, González-Fernández, Martín, Gogola, Ewa, Siffert, Myriam, Buchs, Natasha, Braga-Lagache, Sophie, Uldry, Anne-Christine, Jonkers, Jos, Heller, Manfred, Rottenberg, Sven
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 06.10.2025 Nature Publishing Group Nature Portfolio
Témata:	14 14/34 45 45/41 631/337/458/1275 631/67/1059/2326 64/110 82 82/58 Acetylation Acetyltransferase Acetyltransferases - genetics Acetyltransferases - metabolism Animals Antineoplastic Agents - pharmacology Biomedical and Life Sciences BRCA1 protein Breast cancer Cancer therapies Carboplatin Carboplatin - pharmacology Cell Line, Tumor Cells Cisplatin - pharmacology CRISPR DNA damage DNA repair Drug resistance Drug Resistance, Neoplasm Genomes Golgi apparatus Humans Life Sciences Membrane Proteins - genetics Membrane Proteins - metabolism Mice N-terminal acetyltransferase Ovarian cancer p53 Protein Platinum Proteins Tumors
ISSN:	2399-3642, 2399-3642
On-line přístup:	Získat plný text
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Shrnutí:	The platinum-based drugs cis- and carboplatin, which are crucial for treating cancers with DNA repair defects, like those caused by BRCA1/2 mutations, rely on the volume-regulated anion channel subunits LRRC8A and LRRC8D for about 50% of cellular drug uptake. 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. Genome-wide CRISPR/Cas9 screening identifies the N-terminal acetyltransferase NAA60 to facilitate cis- and carboplatin drug sensitivity, most likely by neutralizing Nt acetylation of the LRRC8A/D VRAC subunits regulating substrate permeability.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2399-3642 2399-3642
DOI:	10.1038/s42003-025-08826-x