Abstract
The immune system is unique among all biological sub-systems in its usage of DNA-editing enzymes to introduce targeted gene mutations and double-strand DNA breaks to diversify antigen receptor genes and combat viral infections. These processes, initiated by specific DNA-editing enzymes, often result in mistargeted induction of genome lesions that initiate and drive cancers. Like other molecules involved in human health and disease, the DNA-editing enzymes of the immune system have been intensively studied in humans and mice, with little attention paid (< 1% of published studies) to the same enzymes in evolutionarily distant species. Here, we present a systematic review of the literature on the characterization of one such DNA-editing enzyme, activation-induced cytidine deaminase (AID), from an evolutionary comparative perspective. The central thesis of this review is that although the evolutionary comparative approach represents a minuscule fraction of published works on this and other DNA-editing enzymes, this approach has made significant impacts across the fields of structural biology, immunology, and cancer research. Using AID as an example, we highlight the value of the evolutionary comparative approach in discoveries already made, and in the context of emerging directions in immunology and protein engineering. We introduce the concept of 5-dimensional (5D) description of protein structures, a more nuanced view of a structure that is made possible by evolutionary comparative studies. In this higher dimensional view of a protein’s structure, the classical 3-dimensional (3D) structure is integrated in the context of real-time conformations and evolutionary time shifts (4th dimension) and the relevance of these dynamics to its biological function (5th dimension).
Highlights
The adaptive immune system in its classical mammalian form first appeared in the common ancestor of all jawed vertebrates, with the cartilaginous fish being the first extant animals to evolve somatically diversified lymphocyte (B and temperature of maximum stability (Ts) cell) receptors (BCR or antibodies, and T cell receptor (TCR), respectively) [1]
In the remainder of this article, because our work has mostly focused on activation-induced cytidine deaminase (AID), we will use this enzyme as a representative example of a genomeediting enzyme that has been extensively studied for 20 years [since its discovery in 1999 – [12, 13]] in the fields of immunity, cancer, DNA damage/repair, and epigenetics
We proposed that due to the potential danger of AID/APOBEC activity for genomic DNA, this inherent structural regulatory mechanism is in place as a safe-guard mechanism in AID and in the tumorigenic A3 family members; the main pillar of this hypothesis was that the open:closed dynamic ratio in AID, A3A and A3B correlated with their catalytic rates and with their relative responsibility for mediating tumorigenic mutations in cancers
Summary
The adaptive immune system in its classical mammalian form first appeared in the common ancestor of all jawed vertebrates (gnathostomes), with the cartilaginous fish being the first extant animals to evolve somatically diversified lymphocyte (B and T cell) receptors (BCR or antibodies, and TCR, respectively) [1]. These studies provide strong opposition to the view that CSR mediation by AID requires a specific set of protein co-factors, because early fish AID are presumably not co-evolved with such presumed co-factors required to chaperone AID to switch regions of the Ig genes in mouse cells These findings are in line with later findings that the role of AID in mediating CSR is simple dC mutation and DSB generation, and that likely AID is targeted to these regions through the abundance of ssDNA structures such as R-loops and DNA/RNA hybrids that are inherently favored by AID [143, 175, 176]. These results showed for the first time that lamprey has more than just one version of a CDA1 enzyme, and remarkably, that these are variably expressed in individuals of the same species, a novel biological phenomenon the mechanism and importance of which is yet to be discovered
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