David H Dreyfus1. 1. Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut 06511, USA. dhdreyfus@pol.net
Abstract
BACKGROUND: The RAG proteins required for V(D)J recombination of immunoglobulin and T-cell receptor genes in the acquired immune response contain a magnesium ion-binding site termed a DDE site, composed of D (aspartic acid) and E (glutamic acid) amino acids. A similar DDE-like magnesium binding site also is present in transposases, retroviral integrases, and the innate antiviral response enzymes RNAse H and RNA-induced silencing complex (RISC). OBJECTIVE: To help clinicians understand immunodeficiency that results from deficiencies of RAG protein functions, such as severe combined immunodeficiency disorders, Omenn syndrome, and ataxia telangiectasia, and to be familiar with the diverse roles of other DDE enzymes. METHODS: Literature published in peer-reviewed journals during the past 2 decades that identified and characterized DDE enzymes, including RAG proteins, RISC and RNA silencing, RNAse H, retroviral integrases, transposases, and a putative DDE recombinase required for herpes virus replication, was selectively reviewed and summarized by the author. RESULTS: DDE enzymes play a critical role in acquired immunity through RAG-mediated immunoglobulin and T-cell receptor V(D)J recombination in innate immunity through RISC and RNAse H. Paradoxically, DDE enzymes are critical components of pathogen-specific enzymes such as retroviral integrase and other pathogen-encoded proteins. CONCLUSION: Because of their critical role in acquired and innate immunity, the DDE recombinases are attractive targets for novel pharmacologic therapies. Currently, retroviral integrase inhibitors in clinical trial for human immunodeficiency virus infection appear to be safe and effective and could provide a paradigm for inactivating DDE sites in other viral pathogens, as well as RAG and RISC.
BACKGROUND: The RAG proteins required for V(D)J recombination of immunoglobulin and T-cell receptor genes in the acquired immune response contain a magnesium ion-binding site termed a DDE site, composed of D (aspartic acid) and E (glutamic acid) amino acids. A similar DDE-like magnesium binding site also is present in transposases, retroviral integrases, and the innate antiviral response enzymes RNAse H and RNA-induced silencing complex (RISC). OBJECTIVE: To help clinicians understand immunodeficiency that results from deficiencies of RAG protein functions, such as severe combined immunodeficiency disorders, Omenn syndrome, and ataxia telangiectasia, and to be familiar with the diverse roles of other DDE enzymes. METHODS: Literature published in peer-reviewed journals during the past 2 decades that identified and characterized DDE enzymes, including RAG proteins, RISC and RNA silencing, RNAse H, retroviral integrases, transposases, and a putative DDE recombinase required for herpes virus replication, was selectively reviewed and summarized by the author. RESULTS: DDE enzymes play a critical role in acquired immunity through RAG-mediated immunoglobulin and T-cell receptor V(D)J recombination in innate immunity through RISC and RNAse H. Paradoxically, DDE enzymes are critical components of pathogen-specific enzymes such as retroviral integrase and other pathogen-encoded proteins. CONCLUSION: Because of their critical role in acquired and innate immunity, the DDE recombinases are attractive targets for novel pharmacologic therapies. Currently, retroviral integrase inhibitors in clinical trial for human immunodeficiency virus infection appear to be safe and effective and could provide a paradigm for inactivating DDE sites in other viral pathogens, as well as RAG and RISC.