dna repair 6 ( 2 0 0 7 ) 505–516 available at www.sciencedirect.com journal homepage: www.elsevier.com/locate/dnarepair Uracil in DNA—General mutagen, but normal intermediate in acquired immunity Bodil Kavli ∗ , Marit Otterlei, Geir Slupphaug, Hans E. Krokan Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, N-7006 Trondheim, Norway article info Article history: Published on line 20 November 2006 Keywords: Uracil in DNA Uracil-DNA glycosylase Somatic hypermutation Class switch recombination B cell lymphoma abstract Deamination of cytosine in DNA results in mutagenic U:G mispairs, whereas incorporation of dUMP leads to U:A pairs that may be genotoxic directly or indirectly. In both cases, uracil is mainly removed by a uracil-DNA glycosylase (UDG) that initiates the base excision repair pathway. The major UDGs are mitochondrial UNG1 and nuclear UNG2 encoded by the UNG- gene, and nuclear SMUG1. TDG and MBD4 remove uracil from special sequence contexts, but their roles remain poorly understood. UNG2 is cell cycle regulated and has a major role in post-replicative removal of incorporated uracils. UNG2 and SMUG1 are both important for prevention of mutations caused by cytosine deamination, and their functions are non- redundant. In addition, SMUG1 has a major role in removal of hydroxymethyl uracil from oxidized thymines. Furthermore, UNG-proteins and SMUG1 may have important functions in removal of oxidized cytosines, e.g. isodialuric acid, alloxan and 5-hydroxyuracil after exposure to ionizing radiation. UNG2 is also essential in the acquired immune response, including somatic hypermutation (SHM) required for antibody affinity maturation and class switch recombination (CSR) mediating new effector functions, e.g. from IgM to IgG. Upon antigen exposure B-lymphocytes express activation induced cytosine deaminase that gen- erates U:G mispairs at the Ig locus. These result in GC to AT transition mutations upon DNA replication and apparently other mutations as well. Some of these may result from the generation of abasic sites and translesion bypass synthesis across such sites. SMUG1 can not complement UNG2 deficiency, probably because it works very inefficiently on single- stranded DNA and is down-regulated in B cells. In humans, UNG-deficiency results in the hyper IgM syndrome characterized by recurrent infections, lymphoid hyperplasia, extremely low IgG, IgA and IgE and elevated IgM. Ung -/- mice have a similar phenotype, but in addition display dysregulated cytokine production and develop B cell lymphomas late in life. © 2006 Elsevier B.V. All rights reserved. 1. Introduction The RNA base uracil may be present in DNA in small amounts as a result of cytosine deamination or misincorporation of dUMP during DNA replication. Such lesions are normally faith- fully repaired by base excision repair (BER) initiated by a uracil- DNA glycosylase [1]. Contrary to expectations, mice deficient ∗ Corresponding author. Tel.: +47 72 573221; fax: +47 72 576400. E-mail address: bodil.kavli@ntnu.no (B. Kavli). in the major uracil-DNA glycosylase encoded by the Ung-gene are viable, fertile and develop normally [2]. This is probably due to the existence of at least three alternative uracil-DNA glycosylases named SMUG1 (single strand selective mono- functional uracil-DNA glycosylase), TDG (thymine/uracil mis- match DNA glycosylase) and MBD4 (methyl binding domain 4 protein) [1]. These apparently have specialized functions but 1568-7864/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.dnarep.2006.10.014