Uracil: Different sources in DNA and Role in Adaptive Immunity

General Description

Uracil can be found in DNA from sources like dUTP incorporation during replication and cytosine deamination, potentially leading to mutagenic events. Understanding these sources is crucial for studying DNA repair and mutagenesis. In adaptive immunity, uracil's involvement in antibody diversification is vital. Enzymes like UNG2 play a dual role in DNA repair and antibody processes, ensuring genomic integrity and antibody diversity. UNG2 deficiency affects immunoglobulin levels and immune responses. Further research is needed to fully grasp UNG2's functions in adaptive immunity. Overall, uracil-DNA glycosylases are pivotal in maintaining DNA integrity and facilitating immune responses against pathogens.

Figure 1. Uracil

Different sources in DNA

Uracil, a common RNA base that is typically replaced by thymine in DNA, can be found in cellular or viral DNA from various sources. One significant source of uracils in DNA is the incorporation of dUTP by polymerases during replication. This incorporation can lead to the formation of U:A pairs, which can affect promoter functions but are generally non-mutagenic. However, if uracils are not repaired and lead to chromosomal abasic sites, they can become cytotoxic or mutagenic, particularly resulting in G-to-A transition mutations. Another source of uracils in DNA is the deamination of cytosine to uracil, which can occur spontaneously or enzymatically. Spontaneous deamination of cytosine is a common event, happening numerous times per cell per day. Enzymes like (cytosine-5)-methyltransferase and APOBEC cytidine deaminases can also convert cytosine to uracil, leading to potential mutagenic events. The misincorporation of uracil residues in DNA can have significant consequences. The de novo synthesis of ribonucleotides and deoxyribonucleotides in cells contributes to the formation of dUTP, which can be mistakenly incorporated into DNA due to the inability of DNA polymerases to distinguish between dUTP and dTTP. This misincorporation can lead to mutations during DNA replication. Overall, uracils in DNA can originate from the incorporation of dUTP during replication or the deamination of cytosine residues. These uracils can impact DNA integrity and function, potentially leading to mutagenic events and affecting cellular processes. Understanding the different sources of uracils in DNA is crucial for studying DNA repair mechanisms, mutagenesis, and the role of uracils in cellular and viral genomes. ¹

Role in Adaptive Immunity

Uracil plays a crucial role in adaptive immunity through its involvement in the antibody diversification process. Eukaryotic and prokaryotic cells have developed mechanisms to prevent the presence of uracils in DNA due to the harmful effects of unrepaired genomic uracils. One such mechanism involves the action of dUTPase, an enzyme that regulates the intracellular pool of dUTP by converting it to dUMP, thereby maintaining genomic stability. In the event that uracil is present in DNA, the base excision repair (BER) pathway is activated. This repair process involves the recognition and excision of uracil by specific DNA glycosylases, such as UNG2, leading to the formation of an abasic site. Subsequent cleavage by endonucleases and polymerases results in the removal of the uracil-containing fragment and the synthesis of new DNA to repair the damage. UNG2, along with other enzymes like REV1 and pol η, plays a key role in the repair of uracil lesions, ensuring the integrity of the DNA. Moreover, UNG2 is not only involved in DNA repair but also plays a critical role in antibody diversification. During somatic hypermutation (SHM) and class-switch recombination (CSR) processes in B cells, uracil lesions generated by AID within the Ig locus are recognized and excised by UNG2. This initiates a series of events leading to the generation of diverse antibody molecules with enhanced affinity and effector functions, crucial for combating pathogens. UNG2-deficient individuals exhibit defects in antibody diversification, leading to altered levels of immunoglobulins and compromised immune responses. In conclusion, uracil-DNA glycosylases' dual role in DNA repair and antibody diversification underscores its significance in adaptive immunity against various pathogens. Further research is needed to fully elucidate the mechanisms underlying UNG2's function in these processes and its potential implications for immune responses. ²

Reference

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2. Hagen L, Peña-Diaz J, Kavli B, Otterlei M, Slupphaug G, Krokan HE. Genomic uracil and human disease. Exp Cell Res. 2006; 312(14): 2666-2672.