Department of Molecular Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0347, USA.
Medical Research Council, Laboratory for Molecular Cell Biology, University College London, London, WC1E 6BT, UK.
Sci Rep. 2024 Sep 30;14(1):22629. doi: 10.1038/s41598-024-72394-z.
The emerging class of multi-functional proteins known as moonlighters challenges the "one protein, one function" mentality by demonstrating crosstalk between biological pathways that were previously thought to be functionally discrete. Here, we present new links between amino acid metabolism and chromatin regulation, two biological pathways that are critical for cellular and organismal homeostasis. We discovered that the threonine biosynthetic pathway is required for the transcriptional silencing of ribosomal DNA (rDNA) in Saccharomyces cerevisiae. The enzymes in the pathway promote rDNA silencing through distinct mechanisms as a subset of silencing phenotypes was rescued with exogenous threonine. In addition, we found that a key pathway enzyme, homoserine dehydrogenase, promotes DNA repair through a mechanism involving the MRX complex, a major player in DNA double strand break repair. These data further the understanding of enzymes with non-canonical roles, here demonstrated within the threonine biosynthetic pathway, and provide insight into their roles as potential anti-fungal pharmaceutical targets.
新兴的多功能蛋白类群——“月亮族蛋白”（moonlighters）挑战了“一种蛋白，一种功能”的传统观念，其蛋白能够在先前被认为功能上相互独立的生物途径之间进行交流。在这里，我们呈现了氨基酸代谢和染色质调控这两个对细胞和生物整体稳态至关重要的生物途径之间的新联系。我们发现苏氨酸生物合成途径对于酿酒酵母核糖体 DNA（rDNA）的转录沉默是必需的。该途径中的酶通过不同的机制促进 rDNA 沉默，因为一组沉默表型可以通过外源性苏氨酸得到挽救。此外，我们发现该途径中的关键酶——高丝氨酸脱氢酶，通过一种涉及 MRX 复合物的机制促进 DNA 修复，MRX 复合物是 DNA 双链断裂修复的主要参与者。这些数据进一步加深了对具有非典型作用的酶的理解，在这里，在苏氨酸生物合成途径中得到了证明，并为它们作为潜在的抗真菌药物靶点的作用提供了新的认识。
