Arnesen T, Gromyko D, Pendino F, Ryningen A, Varhaug J E, Lillehaug J R
Department of Molecular Biology, University of Bergen, Norway.
Oncogene. 2006 Jul 20;25(31):4350-60. doi: 10.1038/sj.onc.1209469. Epub 2006 Mar 6.
Protein N-epsilon-acetylation is recognized as an important modification influencing many biological processes, and protein deacetylase inhibitors leading to N-epsilon-hyperacetylation of histones are being clinically tested for their potential as anticancer drugs. In contrast to N-epsilon-acetyltransferases, the N-alpha-acetyltransferases transferring acetyl groups to the alpha-amino groups of protein N-termini have only been briefly described in mammalians. Human arrest defective 1 (hARD1), the only described human enzyme in this class, complexes with N-acetyltransferase human (NATH) and cotranslationally transfers acetyl groups to the N-termini of nascent polypeptides. Here, we demonstrate that knockdown of NATH and/or hARD1 triggers apoptosis in human cell lines. Knockdown of hARD1 also sensitized cells to daunorubicin-induced apoptosis, potentially pointing at the NATH-hARD1 acetyltransferase complex as a novel target for chemotherapy. Our results argue for an essential role of the NATH-hARD1 complex in cell survival and underscore the importance of protein N-alpha-acetylation in mammalian cells.
蛋白质N-ε-乙酰化被认为是一种影响许多生物过程的重要修饰，导致组蛋白N-ε-超乙酰化的蛋白质脱乙酰酶抑制剂正在作为抗癌药物进行临床试验。与N-ε-乙酰转移酶不同，将乙酰基转移到蛋白质N末端α-氨基上的N-α-乙酰转移酶在哺乳动物中仅被简要描述过。人类 Arrest defective 1（hARD1）是该类别中唯一被描述的人类酶，它与人类N-乙酰转移酶（NATH）形成复合物，并在共翻译过程中将乙酰基转移到新生多肽的N末端。在这里，我们证明敲低NATH和/或hARD1会触发人类细胞系中的细胞凋亡。敲低hARD1还会使细胞对柔红霉素诱导的细胞凋亡敏感，这可能表明NATH-hARD1乙酰转移酶复合物是化疗的新靶点。我们的结果表明NATH-hARD1复合物在细胞存活中起着至关重要的作用，并强调了蛋白质N-α-乙酰化在哺乳动物细胞中的重要性。
