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2015 ; 43
(22
): 10633-54
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Comparative genomic analyses reveal a vast, novel network of nucleotide-centric
systems in biological conflicts, immunity and signaling
#MMPMID26590262
Burroughs AM
; Zhang D
; Schäffer DE
; Iyer LM
; Aravind L
Nucleic Acids Res
2015[Dec]; 43
(22
): 10633-54
PMID26590262
show ga
Cyclic di- and linear oligo-nucleotide signals activate defenses against invasive
nucleic acids in animal immunity; however, their evolutionary antecedents are
poorly understood. Using comparative genomics, sequence and structure analysis,
we uncovered a vast network of systems defined by conserved prokaryotic
gene-neighborhoods, which encode enzymes generating such nucleotides or
alternatively processing them to yield potential signaling molecules. The
nucleotide-generating enzymes include several clades of the DNA-polymerase ?-like
superfamily (including Vibrio cholerae DncV), a minimal version of the CRISPR
polymerase and DisA-like cyclic-di-AMP synthetases. Nucleotide-binding/processing
domains include TIR domains and members of a superfamily prototyped by Smf/DprA
proteins and base (cytokinin)-releasing LOG enzymes. They are combined in
conserved gene-neighborhoods with genes for a plethora of protein superfamilies,
which we predict to function as nucleotide-sensors and effectors targeting
nucleic acids, proteins or membranes (pore-forming agents). These systems are
sometimes combined with other biological conflict-systems such as
restriction-modification and CRISPR/Cas. Interestingly, several are coupled in
mutually exclusive neighborhoods with either a prokaryotic ubiquitin-system or a
HORMA domain-PCH2-like AAA+ ATPase dyad. The latter are potential precursors of
equivalent proteins in eukaryotic chromosome dynamics. Further, components from
these nucleotide-centric systems have been utilized in several other systems
including a novel diversity-generating system with a reverse transcriptase. We
also found the Smf/DprA/LOG domain from these systems to be recruited as a
predicted nucleotide-binding domain in eukaryotic TRPM channels. These findings
point to evolutionary and mechanistic links, which bring together CRISPR/Cas,
animal interferon-induced immunity, and several other systems that combine
nucleic-acid-sensing and nucleotide-dependent signaling.