An Evolutionary View of the Mechanism for Immune and Genome Diversity

Abstract

An ortholog of activation-induced cytidine deaminase (AID) was, evolutionarily, the first enzyme to generate acquired immune diversity by catalyzing gene conversion and probably somatic hypermutation (SHM). AID began to mediate class switch recombination (CSR) only after the evolution of frogs. Recent studies revealed that the mechanisms for generating immune and genetic diversity share several critical features. Meiotic recombination, V(D)J recombination, CSR, and SHM all require H3K4 trimethyl histone modification to specify the target DNA. Genetic instability related to dinucleotide or triplet repeats depends on DNA cleavage by topoisomerase 1, which also initiates DNA cleavage in both SHM and CSR. These similarities suggest that AID hijacked the basic mechanism for genome instability when AID evolved in jawless fish. Thus, the risk of introducing genome instability into nonimmunoglobulin loci is unavoidable but tolerable compared with the advantage conferred on the host of being protected against pathogens by the enormous Ig diversification.

Repair of Oxidative DNA Damage and Cancer: Recent Progress in DNA Base Excision Repair

“…However, it is now clear that conservation between E. coli and the higher eukaryotes is limited, and that many mammalian specific factors and reactions are necessary for the whole BER pathway. In addition, the activity of BER to ''edit'' small base adducts and damage is utilized for nonrepair activity in the cells, for example, inducing hypermutability in immunoglobulin genes (74) and maintaining demethylated status of cytosine in the genome (32,54,63,118). Conversely, it can also be argued that the high conservation of essential BER genes from prokaryotes to humans underscores the importance of BER for maintenance of genome integrity.…”

APE1 is dispensable for S-region cleavage but required for its repair in class switch recombination

“…Because AID is known to introduce DNA cleavage in a limited number of non-Ig genes such as oncogene c-myc, AID targets are restricted (20). There are only a small number of enzymes that can cause DNA damage (genotoxic activity) in a transcription-dependent manner.…”

Functional requirements of AID’s higher order structures and their interaction with RNA-binding proteins

“…Because the AID C-terminal mutants were all shown to be monomeric, their wide distribution along the gradient suggested that some of the monomers associated with other proteins and RNAs. Collectively, these results showed that AID distributed in the LMW region could be subdivided into a narrow region of exclusive monomer (fractions 3-4) and a broader region of monomer and dimer (fractions [5][6][7][8][9][10][11][12] and that the HMW fractions of AID seemed to contain dimers.…”

“…In the present study, we demonstrated that specific AID-associated RBPs have the potential to direct AID's function toward either DNA cleavage or recombination. Because CSR recombination can be regulated at either the S-S synapse or the DNA end-processing repair phase (6,11,12), we speculate that at least two independent mRNAs are involved (7,11,60). Thus, it is reasonable to propose that distinct RBPs are involved in AID-RNP complex formation and that their KD affects different stages of CSR.…”

“…Although both processes are initiated by AID-induced DNA cleavage, point mutations at the V region are executed mostly by error-prone DNA repair whereas CSR is accomplished by recombination of cleaved ends at donor and acceptor S regions (5,6). However, the detailed mechanisms by which AID carries out the two mechanistically distinct functions for SHM and CSR have yet to be uncovered (7). Studies on AID mutants revealed that AID's N-and C-terminal domains are distinctly required for its DNA-cleavage and recombination functions, respectively (8)(9)(10).…”