A5102005709- DNA Repair Mechanisms
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Genetic factors in colorectal cancer
- Cancer Genomics and Diagnostics
- Evolution and Genetic Dynamics
- PARP inhibition in cancer therapy
- Immunotherapy and Immune Responses
- Insect-Plant Interactions and Control
- Insect symbiosis and bacterial influences
- Monoclonal and Polyclonal Antibodies Research
- Wnt/β-catenin signaling in development and cancer
- RNA and protein synthesis mechanisms
- Polyomavirus and related diseases
- Cancer Cells and Metastasis
- CRISPR and Genetic Engineering
- Insect and Pesticide Research
- Cancer-related Molecular Pathways
- Transgenic Plants and Applications
- Childhood Cancer Survivors' Quality of Life
- Insect behavior and control techniques
- Chronic Lymphocytic Leukemia Research
- T-cell and Retrovirus Studies
- RNA modifications and cancer
National Institute on Aging
2004-2022
National Institutes of Health
2004-2022
MRC Laboratory of Molecular Biology
2014
Bio-oriented Technology Research Advancement Institution
2005
Osaka University
2005
Japan Science and Technology Agency
2005
University of Chicago
1998-1999
Somatic hypermutation is initiated by activation-induced cytidine deaminase (AID), and occurs in several kilobases of DNA around rearranged immunoglobulin variable (V) genes switch (S) sites before constant genes. AID deaminates cytosine to uracil, which can produce mutations C:G nucleotide pairs, the mismatch repair protein Msh2 participates generating substitutions downstream A:T pairs. always found as a heterodimer with either Msh3 or Msh6, so it important know one involved. Therefore, we...
Hypermutation in immunoglobulin genes produces a high frequency of substitutions all four bases, which are likely generated by low-fidelity DNA polymerases. Indeed, humans deficient for polymerase (pol) η have decreased A·T base pairs variable and switch regions. To study the role pol genetically tractable system, we created mice lacking η. B cells from Polh -/- produced normal amounts IgG, indicating that does not affect class recombination. Similar to their human counterparts, regions had...
Activation-induced deaminase (AID) deaminates cytosine to uracil in immunoglobulin genes. Uracils DNA can be recognized by glycosylase and abasic endonuclease produce single-strand breaks. The breaks are repaired either faithfully base excision repair (BER) or mutagenically somatic hypermutation (SHM) class switch recombination (CSR). To unravel the interplay between mutagenesis, we decreased level of x-ray cross-complementing 1 (XRCC1), a scaffold protein involved BER. Mice heterozygous for...
Activation-induced cytosine deaminase preferentially deaminates C in DNA on the nontranscribed strand vitro, which theoretically should produce a large increase mutations of during hypermutation immunoglobulin genes. However, bias for has not been observed among variable Therefore, we examined mu and gamma switch regions, can form stable secondary structures, to look mutations. To further simplify pattern, were studied absence polymerase (pol) eta, may substitutions nucleotides downstream C....
Low-fidelity DNA polymerases introduce nucleotide substitutions in immunoglobulin variable regions during somatic hypermutation. Although polymerase (pol) η is the major low-fidelity polymerase, other may also contribute. Existing data are contradictory as to whether pol ζ involved. We reasoned that presence of mask contribution ζ, and therefore we generated mice deficient for heterozygous ζ. The frequency spectra hypermutation was unaltered between Polζ+/− Polη−/− Polζ+/+ clones. However,...
A distinct B cell population marked by elevated CD11c expression is found in patients with systemic lupus erythematosus (SLE). Cells a similar phenotype have been described during chronic infection, but variable gating strategies and nomenclature led to uncertainty of their relationship each other. We isolated hi cells from peripheral blood characterized them using transcriptome IgH repertoire analyses. Gene data revealed the IgD + − subsets were highly other, naive, memory, plasma subsets....
The endocellular microbe Wolbachia pipientis infects a wide variety of invertebrate species, in which its presence is closely linked to form reproductive failure termed cytoplasmic incompatibility (CI). CI renders infected males unable father offspring when mated uninfected females. Because can dramatically affect fitness natural populations, mechanisms that abate have equally large impacts on fitness. We discovered repeated copulation by Wolbachia–infected male Drosophila simulans...
DNA polymerase ι (Pol ι) is an attractive candidate for somatic hypermutation in antibody genes because of its low fidelity. To identify a role Pol ι, we analyzed mutations two strains mice with deficiencies the enzyme: 129 negligible expression truncated and knock-in that express full-length catalytically inactive. Both had normal frequencies spectra variable region, indicating loss did not change overall mutagenesis. We next examined if affected tandem generated by another error-prone...
Wolbachia, a bacterial endosymbiont of diverse arthropods, affects its host's reproduction and so is consequential for fitness. In the fruit fly Drosophila simulans, Wolbachia increases embryonic mortality in crosses infected males with uninfected females, possibly by manipulating proteins host gametes. Preliminary data suggests these include at least two families heat-shock proteins, Hsp70 Hsp90. larvae live within necrotic fruit, which can experience thermal stress that induces Hsp...
Abstract Mammalian ATPase family AAA domain–containing protein 5 (ATAD5) and its yeast homolog enhanced level of genomic instability 1 are responsible for unloading proliferating cell nuclear antigen from newly synthesized DNA. Prior work in HeLa cells showed that a decrease ATAD5 levels resulted accumulation chromatin-bound antigen, slowed division, increased instability. In this study, B heterozygous (Atad5+/m) mice were used to examine the effects decreased proliferation on Ab diversity....
Abstract Activation-induced cytidine deaminase (AID) is required for somatic hypermutation and class switch recombination of Ig genes in B cells. Although AID has been shown to deaminate deoxycytidine deoxyuridine DNA vitro, there no physical evidence increased uracils from cells expressing vivo. We used several techniques detect uracil bases a gene that was actively transcribed Escherichia coli AID. Plasmid containing the digested with uracil-DNA glycosylase remove uracil,...
Somatic hypermutation induced by activation-induced deaminase (AID) occurs at high densities between the Ig V gene promoter and intronic enhancer, which encompasses DNA encoding rearranged exon J intron. It has been proposed that proximity enhancer defines boundaries of mutation in regions. However, depending on used, distance is quite variable may result differential targeting around gene. To examine effect accumulation, we sequenced 320 clones containing different endogenous genes IgH Igκ...
Antibody diversity is initiated by activation-induced deaminase (AID), which deaminates cytosine to uracil in DNA. Uracils the Ig gene loci can be recognized DNA glycosylase (UNG) or mutS homologs 2 and 6 (MSH2-MSH6) proteins, then processed into breaks. Breaks switch regions of H chain locus cause isotype switching have been extensively characterized as staggered blunt double-strand However, breaks V that arise during somatic hypermutation are poorly understood. In this study, we...