Nature communications · 2026
ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Huhn Jacklyn M, Valin Liana, Basse Mary, Sokei Judith, Gabriel Nishanth, Martinez Esteban, Kanefsky Joice S, Stransky Stephanie, Dorrance Adrienne, Garzon Ramiro, Di Marcantonio Daniela, Skorski Tomasz, Goldman Aaron R, Tang Hsin-Yao, Cortellazzi Samuele, di Martino Orsola, Krais John, Sidoli Simone, Ferraro Francesca, Wiest David L, Sykes Stephen M
Аннотация
Proper timing of DNA replication relies on sufficient nucleotide pools and replication machinery. The upstream regulatory programs that support the biomass production needed for DNA replication, particularly in the accelerated growth setting of cancer, remain incompletely defined. Here we show that the transcription factor ATF4 coordinates amino acid and nucleotide metabolism with selective protein synthesis to ensure proper DNA replication initiation and timing in acute leukemia. Specifically, ATF4 promotes the expression of enzymes that biosynthesize amino acids required for nucleotide production and drive the transcription of tRNA charging enzymes that sustain translation of a subset of proteins involved in replication origin firing. Consequently, ATF4 inhibition limits nucleotide biosynthesis and replication machinery, thereby disrupting DNA replication timing and leading to leukemia cell differentiation and death. Our findings indicate that ATF4 coordinates metabolic and translational programs to maintain DNA replication fidelity and the differentiation blockade in leukemia cells.