German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Sci Rep. 2017 Jun 16;7(1):3722. doi: 10.1038/s41598-017-03949-6.
The non-canonical initiation factors DENR and MCTS1 have been linked to cancer and autism. We recently showed in Drosophila that DENR and MCTS1 regulate translation re-initiation on transcripts containing upstream Open Reading Frames (uORFs) with strong Kozak sequences (stuORFs). Due to the medical relevance of DENR and MCTS1, it is worthwhile identifying the transcripts in human cells that depend on DENR and MCTS1 for their translation. We show here that in humans, as in Drosophila, transcripts with short stuORFs require DENR and MCTS1 for their optimal expression. In contrast to Drosophila, however, the dependence on stuORF length in human cells is very strong, so that only transcripts with very short stuORFs coding for 1 amino acid are dependent on DENR and MCTS1. This identifies circa 100 genes as putative DENR and MCTS1 translational targets. These genes are enriched for neuronal genes and G protein-coupled receptors. The identification of DENR and MCTS1 target transcripts will serve as a basis for future studies aimed at understanding the mechanistic involvement of DENR and MCTS1 in cancer and autism.
非规范起始因子 DENR 和 MCTS1 与癌症和自闭症有关。我们最近在果蝇中表明，DENR 和 MCTS1 调节含有强 Kozak 序列（stuORFs）的上游开放阅读框（uORFs）的转录物的翻译重新起始。由于 DENR 和 MCTS1 与医学相关，因此有必要确定人类细胞中依赖 DENR 和 MCTS1 进行翻译的转录物。我们在这里表明，与果蝇一样，短 stuORF 的转录物需要 DENR 和 MCTS1 才能最佳表达。然而，与果蝇不同的是，人类细胞对 stuORF 长度的依赖性非常强，因此只有编码 1 个氨基酸的非常短 stuORF 的转录物依赖于 DENR 和 MCTS1。这确定了大约 100 个基因作为潜在的 DENR 和 MCTS1 翻译靶标。这些基因富含神经元基因和 G 蛋白偶联受体。DENR 和 MCTS1 靶转录物的鉴定将为未来旨在理解 DENR 和 MCTS1 在癌症和自闭症中的机制参与的研究奠定基础。
