DALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine tRNAs for 3-methylcytosine modification.

paper Cited Public

Authors: Lentini, Jenna M; Alsaif, Hessa S; Faqeih, Eissa; Alkuraya, Fowzan S; Fu, Dragony
Year: 2020
Journal: Nature communications
PMID: 32427860
DOI: 10.1038/s41467-020-16321-6
PMCID: PMC7237682

Fig. 1

Human METTL2A/B interacts with DALR anticodon-binding domain containing 3 (DALRD3).a Silver stain analysis of purified Strep-METTL2A, 2B and 6 from human 293T cells. Arrowheads denote bands that are enriched in the METTL2A, 2B and 6 purifications relative to control. Asterisks denote non-specific contaminants found in all three purifications. b Protein matches detected through LC-MS analysis of peptides present in the indicated protein purifications. c Immunoblot analysis of control, METTL2A, METTL2B and METTL6 purifications. The immunoblot was probed with anti-TwinStrep and anti-DALRD3 antibodies. Input represents 1% of total. Asterisk represents non-specific band. Percentage DALRD3 purified represents the fraction of DALRD3 recovered from the total input in each purification. N = 1. d Coverage of the reciprocal purification of DALRD3 in protein samples analyzed by LC-MS. e Schematic of human cytosolic arginyl-tRNA synthetase (RARS), mitochondrial arginyl-tRNA synthetase (RARS2) and DALRD3. Domains are indicated representing mitochondrial targeting signal (MTS), aminoacyl synthetase catalytic core and DALR anticodon-binding domain. Source data are provided as a Source data file.

Fig. 2

DALRD3 forms a complex with METTL2A/B to bind distinct arginine tRNAs.a Immunoblot of Strep-DALRD3 purified from 293T cells expressed alone or in conjunction with FLAG-METTL2A/B. Immunoblot was probed with anti-TwinStrep and anti-FLAG antibodies. Load represents a non-specific protein band detected by the anti-Strep antibody used as load control. b Nucleic acid stain of RNAs extracted from the indicated input or purified samples after denaturing PAGE. The migration pattern of 5.8S rRNA (~150 nt), 5S rRNA (~120 nt) and tRNAs (~70–80 nt) are denoted. c Northern blot analysis of the gel in b using the indicated probes. Input represents 2% of total extracts used for purification. The percentage yield represents the amount of RNA in the Strep purification that was recovered from the total input. The experiment was performed three times with comparable results. Quantification was performed on the blot shown. Source data are provided as a Source data file.

Fig. 3

DALRD3 mediates the binding of METTL2A/B to tRNA-Arg-CCU and UCU.a Immunoblot analysis of the purification of Strep-METTL2A/B expressed alone or with FLAG-DALRD3 from 293T human embryonic cells. The immunoblot was probed with anti-TwinStrep and anti-FLAG antibodies. Load represents a non-specific protein band detected by the anti-Strep antibody used as load control. Input represents 2% of total. b Nucleic acid stain of RNAs extracted from the indicated input or purified samples after denaturing PAGE. The migration pattern of tRNAs (70–80 nt), 5.8S rRNA (~150 nt), and 5 S rRNA (~120 nt) are denoted. c Northern blot analysis of METTL2A/B-associated RNAs with the indicated probes. The known presence or absence of m3C and the METTL enzyme that generates m3C in a given tRNA is denoted on the right. The purification was repeated three times with similar results. Source data are provided as a Source data file.

Fig. 4

The identity of residues 36 and 37 in tRNA-Arg-CCU play a key role in m3C formation by METTL2A/2B in vitro.a Anticodon loops of human tRNA-Arginine isoacceptors and known modifications. b Anticodon loops of in vitro transcribed tRNA-Arg-CCU and variants used in c, d. c, d Primer extension analysis of tRNA-Arg-CCU and variants incubated with either water, vector control eluate, purified METTL2A or METTL2B co-expressed with DALRD3. Primer length, 23 nt. e Quantification of m3C formation in d. Primer extension analysis was performed greater than three times for c and repeated three times for d. Bars represent the standard deviation from the mean. Statistical analysis was performed using one-way ANOVA and significance calculated using Tukey’s multiple comparison test. **P < 0.01. P = 0.0034 for WT versus C32A, 0.0039 for WT versus U36G, 0.0037 for WT versus A37G. Source data are provided as a Source data file.

Fig. 5

DALRD3 is required for efficient m3C formation in arginine tRNAs in vivo.a Immunoblot verification for the loss of DALRD3 expression in human DALRD3-knockout (KO) cell lines compared to wild-type human HAP1 cells. Actin was used as a loading control. Asterisk denotes a non-specific band found in both wild-type and D3-KO cell lysates. b Schematic of the Positive Hybridization in the Absence of Modification (PHA) assay. c Northern blot analysis of PHA probes designed to detect m3C at position 32 and a control probe that hybridizes to a different area of the same tRNA. d Primer extension analysis of the tRNA-Arg-UCU and Arg-CCU harvested from the denoted human HAP1 cell lines. Length of primers; tRNA-Arg-UCU, 24 nt; tRNA-Arg-CCU, 23 nt. e Primer extension analysis of the tRNA-Ser-UGA and Thr-AGU harvested from the denoted human HAP1 cell lines. Length of primers; tRNA-Ser-UGA, 23 nt; tRNA-Thr-AGU, 20 nt. f Schematic of DALRD3 variants used for DALRD3 rescue experiments. g Immunoblot analysis confirming expression of DALRD3 variants in the indicated HAP1 cell lines. h Primer extension analysis of tRNA-Arg-CCU from WT or D3KO HAP1 cell lines stable integrated with the indicated DALRD3 expression constructs. (-RT) represents no reverse transcriptase was added; m3C- 3-Methylcytidine; D- dihydrouridine; t6A- threonylcarbamoyladenosine; > labelled probe. i Quantification of m3C formation in tRNA-Arg-CCU by primer extension. n = 3. Error bars represent standard deviation from the mean. Statistical analysis was performed using one-way ANOVA and significance calculated using Tukey’s multiple comparison test. ****P < 0.0001; ns, non-significant. P = 0.7430 for WT strain + vector versus D3-KO strain + WT-DALRD3. a, (c through e), g, h were repeated three times each with similar results. Source data are provided as a Source data file.

Fig. 6

Identification of a DALRD3 variant linked to developmental delay and epileptic encephalopathy.a Pedigree of the family harboring a nonsense mutation in the DALRD3 gene. b Patients 1 and 2 (P1 and P2) containing the homozygous DALRD3 mutation. c Agile MultiIdeogram output of autozygosity analysis of the study family as a series of block arcs with the two affected individuals represented by the outer two arcs. Autozygous regions from affected individuals are marked as pale blue, those from unaffected individuals as pink, and those homozygous in all affected individuals as dark blue. d Sanger sequencing chromatograms of the indicated individuals from the family in this study along with a wildtype, control individual.

Fig. 7

Lymphoblastoid cell lines derived from patients with the homozygous DALRD3 variant exhibit deficiency in m3C modification in arginine tRNAs.a Immunoblot for the indicated proteins from lysates prepared from LCLs donated from wildtype (WT) individuals and patients P1 and P2 harboring the homozygous DALRD3 mutation. Asterisks (*) represent non-specific bands on either side of the DARLD3 protein. Blot was repeated twice with similar results. b Northern blot analysis using PHA probes designed to detect m3C at position 32 and a control probe that hybridizes to a different area of the same tRNA. Blot was repeated three times with comparable results. c Primer extension analysis of the indicated tRNAs from the denoted human LCLs. (-RT) represents no reverse transcriptase; m3C 3-Methylcytidine; D dihydrouridine; t6A threonylcarbamoyladenosine. > labelled probe. Primer extension analysis of lymphoblastoid cell lines was repeated three times. d Quantification of m3C formation by primer extension for the indicated tRNAs. n = 2. Source data are provided as a Source data file.

#	Section	Preview
0	Introduction	The proper maturation and function of tRNAs has emerged as a critical modulator of biological…
1	Introduction	The 3-methylcytosine (m3C) modification at position 32 of the anticodon loop in certain tRNAs is a…
2	Introduction	In S. cerevisiae, the Trm140p methyltransferase is responsible for m3C formation in tRNA-Ser and Thr…
3	Introduction	synthetase has evolved to recognize the unusually long variable loop and diverse tertiary structure…
4	Introduction	Four human homologs of Trm140p have been identified by sequence homology, which are encoded by the…
5	Introduction	Here, we demonstrate that METTL2A and 2B interact with DALRD3, a previously uncharacterized protein…
6	Results — METTL2 interacts with a putative tRNA-binding protein DALRD3	To identify proteins that interact with human METTL2A or 2B, we generated 293T human embryonic cell…
7	Results — METTL2 interacts with a putative tRNA-binding protein DALRD3	To identify METTL-interacting proteins, the total eluates from each purification were processed for…
8	Results — METTL2 interacts with a putative tRNA-binding protein DALRD3	To confirm the DALRD3 interaction and its specificity, we transiently expressed and purified…
9	Results — METTL2 interacts with a putative tRNA-binding protein DALRD3	DALRD3 is an uncharacterized protein containing a carboxy-terminal sequence homologous to the…
10	Results — The METTL2-DALRD3 complex binds distinct arginine tRNAs	Based upon the structure of S. cerevisiae arginyl-tRNA synthetase, the DALR domain forms a nucleic…
11	Results — The METTL2-DALRD3 complex binds distinct arginine tRNAs	We next examined the RNA species that co-purified with DALRD3 by denaturing PAGE followed by nucleic…
12	Results — The METTL2-DALRD3 complex binds distinct arginine tRNAs	To determine the tRNA-binding specificity of DALRD3, we probed the DALRD3 purifications for distinct…
13	Results — DALRD3 facilitates METTL2A/B binding to tRNA-Arg-CCU and UCU	The co-purification of DALRD3 with METTL2A and 2B along with the distinct tRNA-binding specificity…
14	Results — DALRD3 facilitates METTL2A/B binding to tRNA-Arg-CCU and UCU	Analysis of copurifying RNAs revealed the co-purification of tRNA with both METTL2A and 2B (Fig. 3b,…
15	Results — DALRD3 facilitates METTL2A/B binding to tRNA-Arg-CCU and UCU	Using Northern blot hybridization, we detected low levels of tRNA-Arg-CCU and UCU copurifying with…
16	Results — DALRD3 facilitates METTL2A/B binding to tRNA-Arg-CCU and UCU	The enhancement of METTL2A/B interaction with arginine tRNAs by DALRD3 co-expression provides…
17	Results — DALRD3 facilitates METTL2A/B binding to tRNA-Arg-CCU and UCU	The tRNAs stably associated with METTL2 and/or DALRD3 could represent substrates that have not yet…
18	Results — tRNA sequence requirements for methylation by METTL2-DALRD3	Mammalian genomes express five different tRNA isoacceptors that decode arginine codons but only…
19	Results — tRNA sequence requirements for methylation by METTL2-DALRD3	To test this hypothesis, we probed the methyltransferase activity of METTL2-DALRD3 complexes…

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Dysfunctional tRNA reprogramming and codon-biased translation in cancer.	Dedon PC et al.	—	2022	→
Epitranscriptomics of cardiovascular diseases (Review).	Leptidis S et al.	—	2022	→
Methyltransferase METTL8 is required for 3-methylcytosine modification in human mitochondrial tRNAs.	Lentini JM et al.	—	2022	→
Molecular basis for human mitochondrial tRNA m3C modification by alternatively spliced METTL8.	Huang MH et al.	—	2022	→
RNA nucleotide methylation: 2021 update.	Motorin Y et al.	—	2022	→
Roles and dynamics of 3-methylcytidine in cellular RNAs.	Bohnsack KE et al.	—	2022	→
Synthesis of <i>N</i> <sup>4</sup>-acetylated 3-methylcytidine phosphoramidites for RNA solid-phase synthesis.	Moreno S et al.	—	2022	→
The RNA methyltransferase METTL8 installs m<sup>3</sup>C<sub>32</sub> in mitochondrial tRNAs<sup>Thr/Ser(UCN)</sup> to optimise tRNA structure and mitochondrial translation.	Kleiber N et al.	—	2022	→
THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder.	Broly M et al.	—	2022	→
A natural riboswitch scaffold with self-methylation activity.	Flemmich L et al.	—	2021	→
Evolution of Methyltransferase-Like (METTL) Proteins in Metazoa: A Complex Gene Family Involved in Epitranscriptomic Regulation and Other Epigenetic Processes.	Wong JM et al.	—	2021	→
Modifications of the human tRNA anticodon loop and their associations with genetic diseases.	Zhou JB et al.	—	2021	→
Multi-omics integration of methyltransferase-like protein family reveals clinical outcomes and functional signatures in human cancer.	Campeanu IJ et al.	—	2021	→
Mutually exclusive substrate selection strategy by human m3C RNA transferases METTL2A and METTL6.	Mao XL et al.	—	2021	→
The expanding world of tRNA modifications and their disease relevance.	Suzuki T	—	2021	→