Kochavi Adva, Nagel Remco, Körner Pierre-Rene, Bleijerveld Onno B, Lin Chun-Pu, Huinen Zowi, Malka Yuval, Proost Natalie, van de Ven Marieke, Feng Xiaodong, Navarro Jasmine Montenegro, Pataskar Abhijeet, Peeper Daniel S, Champagne Julien, Agami Reuven
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands.
NKI Proteomics Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
Nucleic Acids Res. 2024 Dec 11;52(22):13964-13979. doi: 10.1093/nar/gkae1110.
Messenger RNA (mRNA) translation is a tightly controlled process frequently deregulated in cancer. Key to this deregulation are transfer RNAs (tRNAs), whose expression, processing and post-transcriptional modifications are often altered in cancer to support cellular transformation. In conditions of limiting levels of amino acids, this deregulated control of protein synthesis leads to aberrant protein production in the form of ribosomal frameshifting or misincorporation of non-cognate amino acids. Here, we studied leucine, an essential amino acid coded by six different codons. Surprisingly, we found that leucine deprivation leads to ribosomal stalling and aberrant protein production in various cancer cell types, predominantly at one codon, UUA. Similar effects were observed after treatment with chemotherapeutic agents, implying a shared mechanism controlling the downstream effects on mRNA translation. In both conditions, a limitation in the availability of tRNALeu(UAA) for protein production was shown to be the cause for this dominant effect on UUA codons. The induced aberrant proteins can be processed and immune-presented as neoepitopes and can direct T-cell killing. Altogether, we uncovered a novel mode of interplay between DNA damage, regulation of tRNA availability for mRNA translation and aberrant protein production in cancer that could be exploited for anti-cancer therapy.
信使核糖核酸（mRNA）翻译是一个受到严格调控的过程，在癌症中常常失调。这种失调的关键在于转运核糖核酸（tRNA），其表达、加工和转录后修饰在癌症中常常发生改变，以支持细胞转化。在氨基酸水平受限的情况下，这种对蛋白质合成的失调控制会导致以核糖体移码或非同源氨基酸错掺入形式出现的异常蛋白质产生。在这里，我们研究了亮氨酸，一种由六个不同密码子编码的必需氨基酸。令人惊讶的是，我们发现亮氨酸剥夺会导致各种癌细胞类型中核糖体停滞和异常蛋白质产生，主要发生在一个密码子UUA处。用化疗药物治疗后也观察到了类似的效果，这意味着存在一种共同机制控制对mRNA翻译的下游影响。在这两种情况下，用于蛋白质生产的tRNALeu(UAA)可用性受限被证明是对UUA密码子产生这种主导效应的原因。诱导产生的异常蛋白质可以被加工并作为新表位进行免疫呈递，还可以指导T细胞杀伤。总之，我们揭示了癌症中DNA损伤、mRNA翻译的tRNA可用性调节和异常蛋白质产生之间一种新的相互作用模式，这种模式可用于抗癌治疗。
