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Alarmones as Vestiges of a Bygone RNA World

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Abstract

All known alarmones are ribonucleotides or ribonucleotide derivatives that are synthesized when cells are under stress conditions, triggering a stringent response that affects major processes such as replication, gene expression, and metabolism. The ample phylogenetic distribution of alarmones (e.g., cAMP, Ap(n)A, cGMP, AICAR, and ZTP) suggests that they are very ancient molecules that may have already been present in cellular systems prior to the evolutionary divergence of the Archaea, Bacteria, and Eukarya domains. Their chemical structure, wide biological distribution, and functional role in highly conserved cellular processes support the possibility that these modified nucleotides are molecular fossils of an epoch in the evolution of chemical signaling and metabolite sensing during which RNA molecules played a much more conspicuous role in biological catalysis and genetic information.

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Acknowledgements

Ricardo Hernández Morales is a doctoral student from the Programa de Doctorado en Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM). Financial support from PAPIIT-UNAM (IN223916) is gratefully acknowledged. We are indebted to Samuel Ponce de León for many insightful discussions, Alberto Vázquez-Salazar for providing useful references for this work, and José Alberto Campillo Balderas, Rodrigo Jácome, and Adriana Benítez for technical support.

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Authors and Affiliations

  1. Facultad de Ciencias, Universidad Nacional Autónoma de México, Cd. Universitaria, 04510, Mexico City, Mexico

    Ricardo Hernández-Morales, Arturo Becerra & Antonio Lazcano

  2. Miembro de El Colegio Nacional, Donceles 104, Centro Histórico, 06000, Mexico City, Mexico

    Antonio Lazcano

Authors
  1. Ricardo Hernández-Morales
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  2. Arturo Becerra
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  3. Antonio Lazcano
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Correspondence to Antonio Lazcano.

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Supplementary Fig. 1

Monophyletic origin of the catalytic core of polymerases and adenylate-, guanylate- and diguanylate cyclases. The universal distribution of the palm domain in all living beings suggests this is a very ancient domain which was duplicated and recruited many times during the evolutionary history of polymerases and cyclases. (TIFF 293 KB)

Supplementary Fig. 2

Common origin of the non-canonical palm and the catalytic site of cGAMP synthase. (A) Structural alignment of non-canonical palm domain (1BPY - yellow color) and catalytic site of cGAMP synthase (4TXY – green color). (B) Representation of the monophyletic origin of the catalytic core of polymerase III and β, and cGAMP synthase. (TIFF 547 KB)

Supplementary Table S1

Diversity of alarmones and the biological processes they regulate. Columns include information about the alarmones, the enzymes involved in their biosynthesis and degradation, the stress condition which lead to an increase in their concentration, and the processes that they regulate as described by the reference in the last column. (XLSX 16 KB)

Supplementary Table S2

Distribution (presence-absence) of biosynthetic and degradative enzymes of alarmones in completely sequenced cellular genomes. In first column are enzymes analyzed in this work. Other columns contain the acronyms for each organism’s genome analyzed. Letter “H” indicates that a homologous hit was found in the genome. Letters in each column of the table represent the acronym for each organism’s genome from KEGG database. (XLSX 1654 KB)

Supplementary Table S3

Alarmone biosynthetic and degradative enzymes and their homologous sequences encoded by dsDNA virus with no RNA stage in their biological cycle. Columns, from left to right, indicate: enzyme code (EC), protein identification code, virus type, viral family, and some parameters used on the search. (XLSX 18 KB)

Supplementary Table S4

Protein domains associated with adenylyl cyclases (class III) and their functions. (XLSX 15 KB)

Supplementary Table S5

Polymerase-mediated reaction and the biosynthetic reactions that produce alarmones. (XLSX 11 KB)

Supplementary Table S6

Hypothetical ribozyme-mediated alarmone-biosynthetic reactions. Ribozymes have the ability to catalyze a considerable number of chemical reactions (Table 1). Some of these reactions such as ribozymic polymerization or self-cleaving could lead to the synthesis and accumulation of alarmones. (XLSX 11 KB)

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Hernández-Morales, R., Becerra, A. & Lazcano, A. Alarmones as Vestiges of a Bygone RNA World. J Mol Evol 87, 37–51 (2019). https://doi.org/10.1007/s00239-018-9883-3

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