Enzymes, proteins, riboproteins and signaling pathways.


Nuclear uracil-DNA glycosylase (UNG2) is a base excision repair enzyme that participates in repair of U/A pairs resulting from misincorporation of dUMP during replication.

Deamination of cytosine (to uracil) occurs at a rate of 100–500 per human cell per day, yielding mutagenic U/G mispairs which, unless repaired, result in G.C to A.T transitions upon replication (1).

Activation-induced (cytidine) deaminase (AID) is a 24 kDa enzyme currently considered the master regulator of secondary antibody diversification because it is involved in the initiation of three distinct immunoglobulin diversification processes: somatic hypermutation (SHM), class-switch recombination (CSR), and gene-conversion (GC). AID-generated somatic hypermutations affect the variable (V) regions of genes encoding immunoglobulins. In antigen-stimulated B-lymphocytes, UNG2 removes uracil from U/G mispairs as part of somatic hypermutation and class-switch recombination processes.

UNG2 is the major enzyme initiating BER of deaminated cytosine (U/G), and may prove the sole enzyme initiating BER of misincorporated uracil (U/A). UNG2 is present in preassembled complexes that are proficient in base excision repair. UNG2-associated repair complexes (UNG2-ARC) carry out short-patch and long-patch base excision repair (BER). The UNG2-associated repair complexes contain proteins required for both types of BER, including UNG2, APE1, POLbeta, POLdelta, XRCC1, PCNA and DNA ligase. Short-patch repair is the predominant mechanism for UNG2-ARC in proliferating cells and in less BER-proficient growth-arrested cells.

Repair of U/G mispairs and U/A pairs can be completely inhibited by neutralizing UNG-antibodies. Recombinant SMUG1 can partially restore repair of U/G mispairs, yet it is unable to restore repair of U/A pairs in UNG2-ARC. Neutralizing antibodies to APE1 and POLbeta, and depletion of XRCC1 strongly reduce short-patch BER, and a fraction of long-patch repair is POLbeta dependent.[r1]

Patients deficient in UNG2 suffer recurrent infections associated with hyper-IgM syndrome, which displays increased IgM, strongly decreased IgG, IgA and IgE and skewed SHM. UNG2 is also important in innate immune response against retroviral infections. Ung(-/-) mice develop B-cell lymphomas late in life, yet there is currently no evidence indicating that UNG deficiency causes lymphomas in humans. Genomic uracil and human disease. Hagen L, Pena-Diaz J,
Kavli B, Otterlei M, Slupphaug G, Krokan HE. Exp Cell Res. 2006 Aug 15;312(14):2666-72. Epub 2006 Jun 21.

[r1] Repair of U/G and U/A in DNA by UNG2-associated repair complexes takes place predominantly by short-patch repair both in proliferating and growth-arrested cells. Akbari M,
Otterlei M, Pena-Diaz J, Aas PA, Kavli B, Liabakk NB, Hagen L, Imai K, Durandy A, Slupphaug G, Krokan HE. Nucleic Acids Res. 2004 Oct 12;32(18):5486-98. Print 2004. [Free Full Text Article]

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