Genomic uracil and human disease.

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Uracil occurs in DNA from cytosine deamination or dUMP incorporation.
• While typically repaired, uracil in DNA plays a crucial role in B-cell adaptive immunity.
• Activation-induced cytosine deaminase (AID) and uracil-DNA glycosylase (UNG2) are key enzymes involved.

Purpose of the Study:

• To elucidate the dual role of uracil in DNA: as a potential mutagen and a physiological intermediate in B-cell immunity.
• To understand the mechanisms of somatic hypermutation (SHM) and class switch recombination (CSR) involving uracil.
• To investigate the consequences of uracil-DNA glycosylase (UNG2) deficiency in immune function and disease susceptibility.

Main Methods:

• Analysis of DNA repair pathways involving uracil.
• Investigating the function of activation-induced cytosine deaminase (AID) and uracil-DNA glycosylase (UNG2) in B-cells.
• Studying phenotypes of patients and mice lacking functional UNG2.

Main Results:

• Uracil in DNA is managed by base excision repair, but also utilized by AID and UNG2 in immunoglobulin loci for SHM and CSR.
• UNG2 deficiency leads to impaired immunoglobulin diversification, a hyper-IgM syndrome, and increased susceptibility to infections.
• While Ung(-/-) mice develop B-cell lymphomas, human UNG2 deficiency is not linked to lymphoma development.

Conclusions:

• Uracil processing by UNG2 is essential for adaptive immunity, specifically for generating antibody diversity and class switching.
• UNG2 plays a critical role in both innate and adaptive immune responses.
• The distinct outcomes of UNG2 deficiency in mice and humans warrant further investigation regarding lymphoma risk.