Human DIMT1 generates N26,6A-dimethylation–containing small RNAs

Shen, Hui; Gonskikh, Yulia; Stoute, Julian; Liu, Kathy Fange

doi:10.1016/j.jbc.2021.101146

Cited by 9 publications

(13 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, our results suggest that certain cell types such as AML cells are more sensitive to DIMT1 deficiency (Figure 1A). In our previous study (Shen et al 2021), we observed that DIMT1 +/-HEK 293T expressing E85A-DIMT1 has reduced translation and cell proliferation compared to DIMT1 +/-HEK 293T expressing the WT-DIMT1. But E85A DIMT1-expressing MOLM-13C cells have indistinguishable cell proliferation from WT-DIMT1 cells.…”

Section: The Rrna Cleft Identified In This Study Is An Achilles' Heel...mentioning

confidence: 83%

“…Previous studies have suggested that DIMT1 is highly expressed in leukemia cells (Shen et al 2021) (https://depmap.org/portal/publications/). CERES score showed moderately higher dependency of leukemia cells on DIMT1 gene compare to all cancers (Supplementary Figure S1A).…”

Section: Resultsmentioning

confidence: 99%

“…We analyzed the residues in DIMT1 which contacts 18 S rRNA. As shown in the structure of DIMT1 (PDB 7MQA) (Shen et al 2021) (Figure 3 A and B), there is a positively charged cleft between the N -terminal domain and the C -terminal domain of DIMT1, which contacts helix 45 in 18 S rRNA. There are five positively charged residues, including Arg162 and Arg174 in the N -terminal domain and Arg228, Lys253, and Arg256 in the C-terminal domain of DIMT1, which are particularly noteworthy for their potential rRNA binding ability (Figure 3B).…”

Section: Resultsmentioning

confidence: 99%

“…Ablation of DIMT1 disrupts ribosome biogenesis, and it is lethal for human cells. Recently, we and others have shown that the catalytic activity of DIMT1 is not required for ribosome biogenesis (Zorbas et al 2015; Shen et al 2020b; Shen et al 2021). Thus, the function of DIMT1-mediated rRNA methylation and DIMT1’s non-catalytic role in rRNA processing and ribosome biogenesis are decoupled.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Non-catalytic regulation of 18SrRNA methyltransferase DIMT1 in acute myeloid leukemia

Gonskikh

Stoute

Shen

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Several rRNA modifying enzymes install rRNA modifications while participating in ribosome assembly. Here, we show that 18S rRNA methyltransferase DIMT1 is essential for acute myeloid leukemia (AML) proliferation through a non-catalytic function. We reveal that targeting a positively charged cleft of DIMT1, remote from the catalytic site, weakens the binding of DIMT1 to rRNA and mis-localizes DIMT1 to the nucleoplasm, in contrast with the primarily nucleolar localization of wild-type DIMT1. Mechanistically, rRNA binding is required for DIMT1 to undergo liquid-liquid phase separation, which explains why the distinct nucleoplasm localization of the rRNA-binding deficient DIMT1. Re-expression of wild-type or a catalytically inactive mutant E85A, but not the rRNA-binding deficient DIMT1, supports AML cell proliferation. This study provides a new strategy to target DIMT1-regulated AML proliferation via targeting this essential non-catalytic region.

show abstract

Section: The Rrna Cleft Identified In This Study Is An Achilles' Heel...mentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Non-catalytic regulation of 18SrRNA methyltransferase DIMT1 in acute myeloid leukemia

Gonskikh

Stoute

Shen

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Dimethyladenosine transferase 1 (dimt1), a conserved RNA methyltransferase (m26,6a), is crucial in ribosome biogenesis, cell viability, and protein synthesis. Dimt1 can also interact with miR-7132a, reflecting the possible connection and potential interaction between them (Shen et al, 2021). Besides, euchromatic histone lysine methyltransferase 2 (Ehmt2/G9a) (Ryu et al, 2022), and Lysine-specific demethylase 2A (KDM2A), (Xu et al, 2019), play important roles in a variety of cancers through regulation in multiple immune-related pathways.…”

Section: Functional Dmrs Related Genes Potentially Interacted With Demsmentioning

confidence: 99%

Integrative sperm DNA methylation and miRomics analysis highlights interaction of two epigenetic patterns of pseudomale inheritance in teleost

Zhao

Chen

et al. 2022

Front. Mar. Sci.

View full text Add to dashboard Cite

Proper DNA methylation in spermatozoa is essential for the normal development of fertilized embryos through gene expression regulation. Abnormal sperm DNA methylation is associated with male fertility impairment, offspring quality decline, and disease susceptibility. Compared with other epigenetic regulatory mechanisms (e.g., histone modification), DNA methylation is a stable regulator for the long-term transcriptional activity of genes. Sperm DNA methylation is crucial to offspring’s survival, development, and reproduction. However, it has not been well studied in teleost to a large extent, especially in some species with sex deviation or congenital sex abnormality in offspring. In the present study, DNA methylation profiles of pseudomale (ZW) and male (ZZ) tongue sole (Cynoglossus semilaevis) spermatozoa were characterized for differential methylation regions (DMRs) screening. The global methylation levels of the two sperm groups were highly methylated with no significant differences. For all kinds of genomic elements, the mean methylation level of the ZW group was higher than that of the ZZ group. The total numbers of Covered C annotated on the W chromosome of both groups were extremely small, suggesting that W-type sperm did not exist in pseudomales. A comparison of methylation levels on 20 sex-related genes between sperm and gonad showed that the heterogeneity between tissue resources was greater than that between sexes, and the methylation level of most genes in gonads was lower than that in sperm. For integrative analysis of DNA methylation and miRomic profiles, 11 sex-related DMRs associated with 15 differentials micro RNAs (miRNAs) in spermatozoa were identified to present targeting relationships and regulatory trends of the two distinct epigenetic patterns. This study provides valuable and potential targets of coordination between two epigenetic mechanisms in the process of C. semilaevis sex congenital bias.

show abstract

AlkB-Facilitated Demethylation Enables Quantitative and Site-Specific Detection of Dual Methylation of Adenosine in RNA

Guo,

Xie,

Chen

et al. 2023

Anal. Chem.

View full text Add to dashboard Cite

RNA molecules undergo various chemical modifications that play critical roles in a wide range of biological processes. N 6 ,N 6 -Dimethyladenosine (m 6,6 A) is a conserved RNA modification and is essential for the processing of rRNA. To gain a deeper understanding of the functions of m 6,6 A, site-specific and accurate quantification of this modification in RNA is indispensable. In this study, we developed an AlkB-facilitated demethylation (AD-m 6,6 A) method for the site-specific detection and quantification of m 6,6 A in RNA. The N 6 ,N 6 -dimethyl groups in m 6,6 A can cause reverse transcription to stall at the m 6,6 A site, resulting in truncated cDNA. However, we found that Escherichia coli AlkB demethylase can effectively demethylate m 6,6 A in RNA, generating full-length cDNA from AlkB-treated RNA. By quantifying the amount of full-length cDNA produced using quantitative real-time PCR, we were able to achieve site-specific detection and quantification of m 6,6 A in RNA. Using the AD-m 6,6 A method, we successfully detected and quantified m 6,6 A at position 1851 of 18S rRNA and position 937 of mitochondrial 12S rRNA in human cells. Additionally, we found that the level of m 6,6 A at position 1007 of mitochondrial 12S rRNA was significantly reduced in lung tissues from sleep-deprived mice compared with control mice. Overall, the AD-m 6,6 A method provides a valuable tool for easy, accurate, quantitative, and site-specific detection of m 6,6 A in RNA, which can aid in uncovering the functions of m 6,6 A in human diseases.

show abstract

Human DIMT1 generates N26,6A-dimethylation–containing small RNAs

Cited by 9 publications

References 51 publications

Non-catalytic regulation of 18SrRNA methyltransferase DIMT1 in acute myeloid leukemia

Non-catalytic regulation of 18SrRNA methyltransferase DIMT1 in acute myeloid leukemia

Integrative sperm DNA methylation and miRomics analysis highlights interaction of two epigenetic patterns of pseudomale inheritance in teleost

AlkB-Facilitated Demethylation Enables Quantitative and Site-Specific Detection of Dual Methylation of Adenosine in RNA

Contact Info

Product

Resources

About