DNA-uracil and human pathology

Sousa, Mirta Mittelstedt Leal de; Krokan, Hans E.; Slupphaug, Geir

doi:10.1016/j.mam.2007.04.006

Cited by 120 publications

(120 citation statements)

References 150 publications

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“…36 It is becoming increasingly apparent, however, that nature incorporates uracil into DNA as a central mediator of adaptive immunity and as a strategy against certain viruses during innate responses. 37,38 Thus, uracil incorporation, once thought to be solely a mutagenic burden, has been revealed as a mechanism to modify immunoglobulin DNA in B cells for diversity or even non-self DNA for degradation. An orthologue of AID has been identified in zebrafish and its expression in mammalian cells in vitro has been shown to induce both CSR and SHM.…”

Section: Discussionmentioning

confidence: 99%

Targets of somatic hypermutation within immunoglobulin light chain genes in zebrafish

Marianes

Zimmerman

2010

Immunology

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Summary In mammals, somatic hypermutation (SHM) of immunoglobulin (Ig) genes is critical for the generation of high‐affinity antibodies and effective immune responses. Knowledge of sequence‐specific biases in the targeting of somatic mutations can be useful for studies aimed at understanding antibody repertoires produced in response to infections, B‐cell neoplasms, or autoimmune disease. To evaluate potential nucleotide targets of somatic mutation in zebrafish (Danio rerio), an enriched IgL cDNA library was constructed and > 250 randomly selected clones were sequenced and analysed. In total, 55 unique VJ‐C sequences were identified encoding a total of 125 mutations. Mutations were most prevalent in VL with a bias towards single base transitions and increased mutation in the complementarity‐determining regions (CDRs). Overall, mutations were overrepresented at WRCH/DGYW motifs suggestive of activation‐induced cytidine deaminase (AID) targeting which is common in mice and humans. In contrast to mammalian models, N and P addition was not observed and mutations at AID hotspots were largely restricted to palindromic WRCH/DGYW motifs. Mutability indexes for di‐ and trinucleotide combinations confirmed C/G targets within WRCH/DGYW motifs to be statistically significant mutational hotspots and showed trinucleotides ATC and ATG to be mutation coldspots. Additive mutations in VJ‐C sequences revealed patterns of clonal expansion consistent with affinity maturation responses seen in higher vertebrates. Taken together, the data reveal specific nucleotide targets of SHM in zebrafish and suggest that AID and affinity maturation contribute to antibody diversification in this emerging immunological model.

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Section: Discussionmentioning

confidence: 99%

Targets of somatic hypermutation within immunoglobulin light chain genes in zebrafish

Marianes

Zimmerman

2010

Immunology

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“…20 Uracil-DNA glycosylase is essential to the generation of somatic hypermutation by generating strand breaks that lead to immunoglobulin heavy chain class switching. 10,21 Individuals deficient in uracil-DNA glycosylase exhibit a hyper-IgM syndrome, with increased IgM levels and decreased IgA and IgG levels. Moreover, mice deficient in UNG develop B-cell lymphomas late in life suggesting a tumor suppressor role for uracil-DNA glycosylase.…”

Section: Discussionmentioning

confidence: 99%

IgA and IgG hypogammaglobulinemia in Waldenstrom's macroglobulinemia

Hunter

Manning²,

Hanzis³

et al. 2009

Haematologica

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“…Uracil in DNA can arise by two mechanisms, cytidine deamination and misincorporation of dUTP. Both mechanisms are potentially mutagenic because of the formation of an AP during their repair (2)(3)(4), and it has been shown that a high intracellular concentration of dUTP is toxic in mammalian cells (5), yeast (6,7), and bacteria (8). It is interesting to note that most DNA polymerases do not discriminate dUTP from deoxythymidine triphosphate (dTTP), as shown by in vitro assays (3).…”

mentioning

confidence: 99%

“…Both mechanisms are potentially mutagenic because of the formation of an AP during their repair (2)(3)(4), and it has been shown that a high intracellular concentration of dUTP is toxic in mammalian cells (5), yeast (6,7), and bacteria (8). It is interesting to note that most DNA polymerases do not discriminate dUTP from deoxythymidine triphosphate (dTTP), as shown by in vitro assays (3). Another argument for the hypothesis that dUTP incorporation could also be involved in SHM is that SHM occurs during phase G 1 of the cell cycle (9,10), during which dUTP concentration is at its peak.…”

mentioning

confidence: 99%

“…dUTP is a physiologic intermediate in pyrimidine metabolism in all organisms. During the G 1 →S transition, the enzyme dUTPase is expressed, which converts dUTP to deoxyuridine monophosphate, the substrate for thymidylate-synthase initiating the synthesis pathway of dTTP (3). In SHM, the uracil in the U:A pair resulting from dUTP incorporation would be recognized by an uracil-DNA glycosylase, forming an AP that would be erroneously repaired in a manner similar to phase I APs.…”

mentioning

confidence: 99%

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Deoxyuridine Triphosphate Incorporation during Somatic Hypermutation of Mouse VkOx Genes after Immunization with Phenyloxazolone

Roche

Claës

Rougeon

2010

The Journal of Immunology

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Somatic hypermutation (SHM) of Ig genes is the result of a two-phase process initiated by activation-induced cytidine deaminase, relying on two different strategies for the introduction of mutations at CG pairs (phase I) and at AT pairs (phase II). To explain the selectivity of phase II, two mechanisms were proposed: AT-selective error-prone DNA-polymerases, deoxyuridine triphosphate (dUTP) incorporation, or both. However, there has been no experimental evidence so far of the possible involvement of the latter. We have developed a ligation-anchored PCR method based on the formation of single-strand breaks at uracils. In this study, we show the presence of uracil in hypermutating VkOx genes in wild type (AID+/+) mice, demonstrating that dUTP incorporation via DNA polymerases could be a major mechanism in SHM. Thus, error-prone DNA polymerases would participate in SHM via low-fidelity replication and incorporation of dUTP.

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DNA-uracil and human pathology

Cited by 120 publications

References 150 publications

Targets of somatic hypermutation within immunoglobulin light chain genes in zebrafish

Targets of somatic hypermutation within immunoglobulin light chain genes in zebrafish

IgA and IgG hypogammaglobulinemia in Waldenstrom's macroglobulinemia

Deoxyuridine Triphosphate Incorporation during Somatic Hypermutation of Mouse VkOx Genes after Immunization with Phenyloxazolone

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