Evolutionarily reinforced GC-rich motif enables non-AUG translation in mammals under eIF1/5MP-mediated fidelity control
Year: 2026
Type: article
Abstract: Non-AUG translation contributes to proteome diversity, but its regulatory principles remain unclear. Here, we show that a GCC-rich upstream extension, termed the NAT1 motif, acts as a potent enhancer of near-cognate initiation in mammals. Cell-free and reporter assays revealed that eIF1 and 5MP act as conserved inhibitors of non-AUG initiation across mammals and plants, while the NAT1 motif enables enhanced initiation within this fidelity framework. Mutational analysis identified −6 and −7 positions within the GCC repeat as key determinants of motif activity. Genome-wide analyses uncovered evolutionary depletion of NAT1 -type non-AUG codons in human 5′UTRs, suggesting purifying selection against excessive initiation. Nevertheless, more than a hundred retained sites are associated with genes involved in cell proliferation and migration, suggesting that regulated non-AUG initiation may contribute to disease-relevant translational programs. The motif’s enrichment within GCC repeats further suggests a mechanistic link to repeat-associated non-AUG translation.
Source: Science Advances
Authors: Haruyuki Furukawa, Abhineet Banerjee, Antonin Tidu, Nirmala Bardiya, Susumu Ishiguro, Chingakham Ranjit Singh, Hitomi Yagi, Hiroyuki Hiraishi, Grant Brooke, Antoine Perret, Kinsley Ochsner, Hailey Casey, Grace Sakai, Megan Freeman, Anastasia Meyer, Keat Robinson, William Finnane, Payton Henderson, Takeru Kameda, Yuichi Togashi, Toshinobu Fujiwara, Franck Martin, Hiroaki Kato, Kazuyuki Takai, Katsura Asano
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
OpenAlex ID: W7225809450