The Dihydrouridine landscape from tRNA to mRNA: a perspective on synthesis, structural impact and function

Abstract

The universal dihydrouridine (D) epitranscriptomic mark results from a reduction of uridine by the Dus family of NADPH-dependent reductases and is typically found within the eponym D-loop of tRNAs. Despite its apparent simplicity, D is structurally unique, with the potential to deeply affect the RNA backbone and many, if not all, RNA-connected processes. The first landscape of its occupancy within the tRNAome was reported 20 years ago. Its potential biological significance was highlighted by observations ranging from a strong bias in its ecological distribution to the predictive nature of Dus enzymes overexpression for worse cancer patient outcomes. The exquisite specificity of the Dus enzymes revealed by a structure-function analyses and accumulating clues that the D distribution may expand beyond tRNAs recently led to the development of new high-resolution mapping methods, including Rho-seq that established the presence of D within mRNAs and led to the demonstration of its critical physiological relevance.

Self-attention enabled deep learning of dihydrouridine (D) modification on mRNAs unveiled a distinct sequence signature from tRNAs

“…Recent studies showed that D is the second most prevalent modification in tRNA. 13 , 14 Catalyzed by D synthases (Dus), D is formed by the hydrogenation of uridine (U) whose C5–C6 bond is reduced, and is found within the eponym D loop of tRNAs. 15 , 16 With its unique structure, D can influence the RNA backbone and a series of RNA-involved processes.…”

“…Furthermore, wet-lab experimental methods such as D sequencing (D-seq) and rhodamine sequencing (Rho-seq) established the presence of D on mRNAs in yeast and human, which further verified its physiological significance. 14 , 23 , 24 Both methods take advantage of D-specific chemistry and next-generation sequencing to determine the location of D across the transcriptome, resulting in high-confidence single-nucleotide-resolution data.…”

“… 33 However, to the best of our knowledge, all existing D-site prediction tools 32 , 33 , 34 , 35 were trained on tRNAs, and it is not clear whether they can be applied to predict D sites on mRNAs. Although recent studies have unveiled the widely occurring nature and transcriptome-wide distribution of D (or the D epitranscriptome), 14 there are still no prediction tools constructed for mRNA D sites using mRNA D datasets.…”

Evolutionary Diversity of Dus2 Enzymes Reveals Novel Structural and Functional Features among Members of the RNA Dihydrouridine Synthases Family

“…Dihydrouridine (D) is one of the most abundant post-transcriptional modified bases in the transcriptome [ 1 , 2 , 3 ]. Present mainly in transfer RNA (tRNA) and occasionally in bacterial ribosomal RNA (rRNA), D has recently entered the messenger RNA (mRNA) world [ 1 , 2 ].…”

“…Dihydrouridine (D) is one of the most abundant post-transcriptional modified bases in the transcriptome [ 1 , 2 , 3 ]. Present mainly in transfer RNA (tRNA) and occasionally in bacterial ribosomal RNA (rRNA), D has recently entered the messenger RNA (mRNA) world [ 1 , 2 ]. Indeed, this modification was recently detected in fission yeast mRNAs, including those encoding cytoskeleton-related proteins (2), in Saccharomyces cerevisiae mRNAs [ 4 ], but also in human mRNAs [ 5 , 6 ].…”