Seetharamsingh Balamkundu

Singapore-MIT Alliance for Research and Technology

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Peter C. Dedon

Massachusetts Institute of Technology

Chuan‐Fa Liu

Chinese University of Hong Kong

Zhenguo Lin

Saint Louis University

Yong Lai

Henan Agricultural University

Timothy K. Lu

Massachusetts Institute of Technology

Ramesh Neelakandan

Nanyang Technological University

Weiling Maggie Cai

Singapore-MIT Alliance for Research and Technology

Luang Xu

Westlake University

Samie R. Jaffrey

Cornell University

Dahai Luo

Nanyang Technological University

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Massachusetts Institute of Technology

Singapore-MIT Alliance for Research and Technology

National University of Singapore

Harvard University Press

University of Florida

Harvard Stem Cell Institute

Nanyang Technological University

Albert Einstein College of Medicine

Cornell University

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Quantifying the RNA cap epitranscriptome reveals novel caps in cellular and viral RNA

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Jin Wang Bing Liang Alvin Chew Yong Lai Hongping Dong Luang Xu

ABSTRACT Chemical modification of transcripts with 5’ caps occurs in all organisms. Here we report a systems-level mass spectrometry-based technique, CapQuant, for quantitative analysis of the cap epitranscriptome in any organism. The method was piloted with 21 canonical caps – m 7 GpppN, m 7 GpppNm, GpppN, GpppNm, and m 2,2,7 GpppG – and 5 “metabolite” caps – NAD, FAD, UDP-Glc, UDP-GlcNAc, and dpCoA. Applying CapQuant to RNA from purified dengue virus, Escherichia coli , yeast, mice, and humans, we discovered four new cap structures in humans and mice (FAD, UDP-Glc, UDP-GlcNAc, and m 7 Gpppm 6 A), cell- and tissue-specific variations in cap methylation, and surprisingly high proportions of caps lacking 2’- O -methylation, such as m 7 Gpppm 6 A in mammals and m 7 GpppA in dengue virus, and we did not detect cap m 1 A/m 1 Am in humans. CapQuant accurately captured the preference for purine nucleotides at eukaryotic transcription start sites and the correlation between metabolite levels and metabolite caps. The mystery around cap m 1 A/m 1 Am analysis remains unresolved.

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10.1101/683045

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Discovery of novel bacterial queuine salvage enzymes and pathways in human pathogens

Proceedings of the National Academy of Sciences (2019)

Yifeng Yuan Rémi Zallot Tyler L. Grove Daniel J. Payan Isabelle Martin‐Verstraete

Queuosine (Q) is a complex tRNA modification widespread in eukaryotes and bacteria that contributes to the efficiency and accuracy of protein synthesis. Eukaryotes are not capable of Q synthesis and rely on salvage of the queuine base (q) as a Q precursor. While many bacteria are capable of Q de novo synthesis, salvage of the prokaryotic Q precursors preQ

10.1073/pnas.1909604116

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7-Deazaguanine modifications protect phage DNA from host restriction systems

Nature Communications (2019)

Geoffrey Hutinet Witold Kot Cui Liang Roman Hillebrand Seetharamsingh Balamkundu

Genome modifications are central components of the continuous arms race between viruses and their hosts. The archaeosine base (G+), which was thought to be found only in archaeal tRNAs, was recently detected in genomic DNA of Enterobacteria phage 9g and was proposed to protect phage DNA from a wide variety of restriction enzymes. In this study, we identify three additional 2'-deoxy-7-deazaguanine modifications, which are all intermediates of the same pathway, in viruses: 2'-deoxy-7-amido-7-deazaguanine (dADG), 2'-deoxy-7-cyano-7-deazaguanine (dPreQ0) and 2'-deoxy-7- aminomethyl-7-deazaguanine (dPreQ1). We identify 180 phages or archaeal viruses that encode at least one of the enzymes of this pathway with an overrepresentation (60%) of viruses potentially infecting pathogenic microbial hosts. Genetic studies with the Escherichia phage CAjan show that DpdA is essential to insert the 7-deazaguanine base in phage genomic DNA and that 2'-deoxy-7-deazaguanine modifications protect phage DNA from host restriction enzymes.

Phagemid

Insert (composites)

genomic DNA

10.1038/s41467-019-13384-y

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Tissue- and sex-specific DNA damage tracks aging in rodents and humans

bioRxiv (Cold Spring Harbor Laboratory) (2022)

Axel Guilbaud Farzan Ghanegolmohammadi Yijun Wang Jiapeng Leng Alexander Kreymerman

Summary DNA damage causes genomic instability underlying many human diseases. Traditional approaches to DNA damage analysis provide minimal insights into the spectrum of disease-driving DNA lesions and the mechanisms causing imbalances in damage formation and repair. Here we used untargeted mass spectrometry-based adductomics 1 to discover 114 putative DNA lesions and modifications consistently detected in humans and two independent analyses in rats, showing species-, tissue-, age-, and sex-biases. As evidence of methodologic rigor, 10 selected adductomic signals were structurally validated as epigenetic marks: 5-MdC, 5-HMdC, 5-FdC; DNA damage products: N 2 -CMdG, 1, N 6 ε-dA, 3, N 4 -εdC, M 1 dG, O 6/ N 2 -MdG, and 8-Oxo-dG; and established analytical artifacts: cyclobutane dimers of 2’-deoxycytosine. With steady-state levels of putative DNA adducts integrating multiple cell types in each tissue, there was strong age-dependent variation for many putative adducts, including N 2 -CMdG, 5-HMdC, and 8-Oxo-dG in rats and 1, N 6 ε-dA in human heart, as well as sex biases for 67 putative adducts in rat tissues. These results demonstrate the potential of untargeted adductomic analysis for defining DNA adducts as disease determinants, assigning substrates to DNA repair pathways, discovering new metabolically-driven DNA lesions, and quantifying inter-individual variation in DNA damage and repair across populations.

genomic DNA

10.1101/2022.11.28.518087

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Quantifying the RNA cap epitranscriptome reveals novel caps in cellular and viral RNA

Nucleic Acids Research (2019)

Jin Wang Bing Liang Alvin Chew Yong Lai Hongping Dong Luang Xu

Chemical modification of transcripts with 5' caps occurs in all organisms. Here, we report a systems-level mass spectrometry-based technique, CapQuant, for quantitative analysis of an organism's cap epitranscriptome. The method was piloted with 21 canonical caps-m7GpppN, m7GpppNm, GpppN, GpppNm, and m2,2,7GpppG-and 5 'metabolite' caps-NAD, FAD, UDP-Glc, UDP-GlcNAc, and dpCoA. Applying CapQuant to RNA from purified dengue virus, Escherichia coli, yeast, mouse tissues, and human cells, we discovered new cap structures in humans and mice (FAD, UDP-Glc, UDP-GlcNAc, and m7Gpppm6A), cell- and tissue-specific variations in cap methylation, and high proportions of caps lacking 2'-O-methylation (m7Gpppm6A in mammals, m7GpppA in dengue virus). While substantial Dimroth-induced loss of m1A and m1Am arose with specific RNA processing conditions, human lymphoblast cells showed no detectable m1A or m1Am in caps. CapQuant accurately captured the preference for purine nucleotides at eukaryotic transcription start sites and the correlation between metabolite levels and metabolite caps.

10.1093/nar/gkz751

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Citations (158)