dU in dsDNA

FULL NAME: 2'-deoxyuridine in double-stranded DNA


DESCRIPTION:
Uracil in DNA results from deamination of cytosine, resulting in mutagenic U : G mispairs, and misincorporation of dUMP, which gives a less harmful U : A pair. At least four different human DNA glycosylases may remove uracil and thus generate an abasic site, which is itself cytotoxic and potentially mutagenic. These enzymes are UNG, SMUG1, TDG and MBD4. The base excision repair process is completed either by a short patch- or long patch pathway, which largely use different proteins. UNG2 is a major nuclear uracil-DNA glycosylase central in removal of misincorporated dUMP in replication foci, but recent evidence also indicates an important role in repair of U : G mispairs and possibly U in single-stranded DNA. SMUG1 has broader specificity than UNG2 and may serve as a relatively efficient backup for UNG in repair of U : G mismatches and single-stranded DNA. TDG and MBD4 may have specialized roles in the repair of U and T in mismatches in CpG contexts. Recently, a role for UNG2, together with activation induced deaminase (AID) which generates uracil, has been demonstrated in immunoglobulin diversification. Studies are now underway to examine whether mice deficient in Ung develop lymphoproliferative malignancies and have a different life span. 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 generates 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. NOTE: URACIL is a common and naturally occurring pyrimidine derivative in which the pyrimidine ring is substituted with two oxo groups at positions 2 and 4. Found in RNA, it base pairs with adenine and replaces thymine during DNA transcription.

DAMAGE TYPE: deamination


DNA DAMAGE SOURCE(S) (MAIN):
spontaneous deamination
DNA replication errors


DNA DAMAGE EFFECT(S) (MAIN):
C→T transition
mutagenesis
point mutation
substitution
transition


PATHWAYS:
base excision repair (BER)


DNA repair protein(s) related to damage:
Ung
Mug


Last modification date: Oct. 4, 2011