The mechanism of V(D)J recombination: site-specificity, reaction fidelity and immunologic diversity

Lieber, Michael R.; Chang, Ching Pin; Gallo, Maria F; Gauss, George H.; Gerstein, Rachel M.; Islas, Ángel L.

doi:10.1006/smim.1994.1020

Cited by 10 publications

(6 citation statements)

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“…Initial analysis of putative P nucleotides in the dataset of 294 human IgM sequences in this study revealed the frequency the presence of putative P nucleotides to be around ten percent of sequences. This is consistent with previous reports [7,10,29]. Statistical analysis of the putative P nucleotides sequences, however, revealed that only one 'P nucleotide sequence' was observed at a frequency that was significantly above the frequency that would be expected from N nucleotide addition alone.…”

Section: Discussionsupporting

confidence: 92%

“…P nucleotide addition has been reported to contribute to diversity in between 10% [7,8,29] and 41% [9] of immunoglobulin sequences. Initial analysis of putative P nucleotides in the dataset of 294 human IgM sequences in this study revealed the frequency the presence of putative P nucleotides to be around ten percent of sequences.…”

Section: Discussionmentioning

confidence: 99%

“…Meier and Lewis observed that putative P nucleotides occur at a significant frequency among the processed recombinant substrates and this has been used as the basis for the allocation of P nucleotides in subsequent immunoglobulin studies [8]. Examination of the frequency of P nucleotides among the recombination substrates, however, revealed a five fold greater frequency of P nucleotide inclusions than was seen among adult murine T cell receptors and immunoglobulin sequences [8] and adult human immunoglobulins [7,29]. The applicability of Meier and Lewis' statistical analysis of the altered recombination substrates to demonstrate the contribution of P nucleotides must therefore be questioned, as the reporting of statistical significance is likely to be a direct result of the elevated frequency of putative P nucleotides among the recombinant substrates.…”

Section: Discussionmentioning

confidence: 99%

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BackgroundImmunoglobulin rearrangement involves random and imprecise processes that act to both create and constrain diversity. Two such processes are the loss of nucleotides through the action of unknown exonuclease(s) and the addition of P nucleotides. The study of such processes has been compromised by difficulties in reliably aligning immunoglobulin genes and in the partitioning of nucleotides between segment ends, and between N and P nucleotides.ResultsA dataset of 294 human IgM sequences was created and partitioned with the aid of a probabilistic model. Non-random removal of nucleotides is seen between the three IGH gene types with the IGHV gene averaging removals of 1.2 nucleotides compared to 4.7 for the other gene ends (p < 0.001). Individual IGHV, IGHD and IGHJ gene subgroups also display statistical differences in the level of nucleotide loss. For example, within the IGHJ group, IGHJ3 has average removals of 1.3 nucleotides compared to 6.4 nucleotides for IGHJ6 genes (p < 0.002). Analysis of putative P nucleotides within the IgM and pooled datasets revealed only a single putative P nucleotide motif (GTT at the 3' D-REGION end) to occur at a frequency significantly higher then would be expected from random N nucleotide addition.ConclusionsThe loss of nucleotides due to the action of exonucleases is not random, but is influenced by the nucleotide composition of the genes. P nucleotides do not make a significant contribution to diversity of immunoglobulin sequences. Although palindromic sequences are present in 10% of immunologlobulin rearrangements, most of the 'palindromic' nucleotides are likely to have been inserted into the junction during the process of N nucleotide addition. P nucleotides can only be stated with confidence to contribute to diversity of less than 1% of sequences. Any attempt to identify P nucleotides in immunoglobulins is therefore likely to introduce errors into the partitioning of such sequences.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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“…V(D)J recombination refers to the combinatorial joining of the variable (V ), diversity (D), and joining (J) BCR and TCR gene segments. 12 Immunoglobulin (Ig) loci are further modified by class switch recombination (CSR), which replaces the heavy chain constant (C H ) region from C to C ␥ , C ␣ , or C ε and results in the production of IgG, IgA, or IgE antibodies, respectively. 13 Finally, the affinity between antibodies and antigens is fine-tuned by the introduction of point mutations in the V region of Igs by the process of somatic hypermutation (SHM).…”

Section: Genetics Of Lymphocyte Developmentmentioning

confidence: 99%

DNA repair: the link between primary immunodeficiency and cancer

Miranda

Björkman

Pan‐Hammarström

2011

Annals of the New York Academy of Sciences

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The adaptive component of the immune system depends greatly on the generation of genetic diversity provided by lymphocyte-specific genomic rearrangements. V(D)J recombination, class switch recombination (CSR), and somatic hypermutation (SHM) constitute complex and vulnerable processes that are orchestrated by a multitude of DNA repair pathways. When inherited defects in certain DNA repair proteins are present, lymphocyte development can be compromised and, consequently, patients can develop primary immunodeficiencies (PIDs). PID patients often have a strong predisposition for cancer development as a result of genomic instability generated from defective DNA repair mechanisms. Tumors of lymphoid origin are one of the most common PID-associated cancers, likely due to DNA lesions resulting from defective V(D)J, CSR, and SHM. In this review, we describe PID syndromes that confer an increased risk for cancer development. Furthermore, we discuss the role of the affected proteins in tumorigenesis/lymphomagenesis.

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“…Ig and TCR variable domains in the antigen recognition region are encoded by variable (V), diversity (D), and joining (J) gene segments. Generation of a functional antigen receptor during lymphocyte differentiation requires the precise assembly of V, D, and J gene segments by a process known as V(D)J recombination [1][2][3][4][5][6]. The gene segments are flanked by recombination signal sequences (RSS) consisting of conserved heptamer and nonamer sequences, CACAGTG and ACAAAAACC, respectively, separated by a spacer seby the recombinase activating proteins 1 and 2 (RAG-1 and RAG-2) [15][16][17][18][19][20][21] while the nonamer sequence is the major recognition site for RAG-1 [18,[22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%