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<p>The platinum-based drugs cis- and carboplatin, which are crucial for treating cancers with DNA repair defects, like those caused by <i>BRCA1/2</i> 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.</p>

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NAA60 facilitates LRRC8A- and LRRC8D-mediated platinum drug uptake

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Carmen Alexandra Widmer,
  • Anna Moyseos,
  • Ismar Klebic,
  • Martina Dettwiler,
  • Martín González-Fernández,
  • Ewa Gogola,
  • Myriam Siffert,
  • Natasha Buchs,
  • Sophie Braga-Lagache,
  • Anne-Christine Uldry,
  • Jos Jonkers,
  • Manfred Heller,
  • Sven Rottenberg

摘要

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.