Site‐specific recombination in the immune system
            <sup>1</sup>

Lieber, Michael R.

doi:10.1096/fasebj.5.14.1752360

Cited by 162 publications

(109 citation statements)

References 52 publications

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“…This larger band could reflect either a second full-length transcript involving another V gene or an abnormally spliced transcript. The smaller transcript would appear to be a nonfunctional joining (J)-C transcript with transcription initiated 5' of germ-line J region genes (14). Neither (16), their ability to endocytose soluble protein (17), and their capacity to act as antigen-presenting cells in an allogeneic mixed lymphocyte reaction when present in very low numbers relative to responder cells (18).…”

Section: Resultsmentioning

confidence: 99%

A murine retrovirus induces proliferation of unique lymphoid cell lines expressing T-cell-receptor structures utilizing common variable region alpha and beta chain genes.

O’Neill¹

1993

Proc. Natl. Acad. Sci. U.S.A.

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A murine radiation leukemia virus (RadLV) has been shown to induce in vitro proliferation of an unusual subset of lymphoid cells from spleen. They have the unusual property of expressing CD3/T-cell receptor a and ,B chains (TCR-a,l) in the absence ofother T-cell markers such as Thy-i, CD4, and CD8. Cell lines induced in two mouse strains with RadLV produced by the C6VL/1 thymoma all specifically utilize common Va3 and V.88.2 variable region genes in the formation of a TCR structure. Each of these cell lines has now been found to express both class I and dass II major histo-

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Section: Resultsmentioning

confidence: 99%

A murine retrovirus induces proliferation of unique lymphoid cell lines expressing T-cell-receptor structures utilizing common variable region alpha and beta chain genes.

O’Neill¹

1993

Proc. Natl. Acad. Sci. U.S.A.

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“…The ensuing repair of the four DNA ends that are produced from a pair of cleavage events results in joining of subexonic coding fragments to form an exon encoding the antigen-binding domain of a B-or T-cell receptor. In contrast, CSR in antigen-stimulated mature B cells is a regionally specific recombination between two repetitive regions [called switch (S) regions] that precede each of the constant regions (1). Looping out intervening sequences between two S regions allows the expression of a new constant region that was further downstream and results in a switch of Ig class (or isotype) from IgM to IgG, IgE, or IgA (2).…”

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confidence: 99%

X-ray repair cross-complementing protein 1 (XRCC1) deficiency enhances class switch recombination and is permissive for alternative end joining

Han

Mao

2012

Proc. Natl. Acad. Sci. U.S.A.

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DNA double-strand breaks (DSBs) are essential intermediates in Ig gene rearrangements: V(D)J and class switch recombination (CSR). In contrast to V(D)J recombination, which is almost exclusively dependent on nonhomologous end joining (NHEJ), CSR can occur in NHEJ-deficient cells via a poorly understand backup pathway (or pathways) often termed alternative end joining (A-EJ). Recently, several components of the single-strand DNA break (SSB) repair machinery, including XRCC1, have been implicated in A-EJ. To determine its role in A-EJ and CSR, Xrcc1 was deleted by targeted mutation in the CSR proficient mouse B-cell line, CH12F3. Here we demonstrate that XRCC1 deficiency slightly increases the efficiency of CSR. More importantly, Lig4 and XRCC1 double-deficient cells switch as efficiently as Lig4-deficient cells, clearly indicating that XRCC1 is dispensable for A-EJ in CH12F3 cells during CSR.A DNA double-strand break (DSB) is one of the most severe forms of DNA damage and can result in chromosome loss or translocations. A variety of endogenous and exogenous sources can induce DSBs, including ionizing radiation, reactive oxygen species, and some chemicals. On the other hand, physiological processes during lymphocyte development such as V(D)J and Ig class switch recombination (CSR) rely on DSBs to rearrange genetic information in somatic cells.V(D)J recombination is a site-specific DNA recombination initiated by the RAG proteins, which are evolved from an ancient DNA transposase. The RAG complex recognizes specific DNA sequences called recombination signal sequences (RSS) and cuts the DNA on one side of the RSS. The ensuing repair of the four DNA ends that are produced from a pair of cleavage events results in joining of subexonic coding fragments to form an exon encoding the antigen-binding domain of a B-or T-cell receptor. In contrast, CSR in antigen-stimulated mature B cells is a regionally specific recombination between two repetitive regions [called switch (S) regions] that precede each of the constant regions (1). Looping out intervening sequences between two S regions allows the expression of a new constant region that was further downstream and results in a switch of Ig class (or isotype) from IgM to IgG, IgE, or IgA (2). CSR is initiated by activation-induced cytidine deaminase (AID) that converts DNA cytosines into uracils at S regions. Through mechanisms that are not yet fully understood, repair of AID-generated uracils in the S region ultimately results in DSBs (2), which serve as critical intermediates in an overall cut-and-paste chromosomal deletion (2).In vertebrate cells, DSB repair mechanisms generally fall into two major categories: homologous recombination (HR) and nonhomologous end joining (NHEJ) (3). HR relies on the presence of another copy of DNA sequences that are highly similar to the one harboring the DSB. Copying genetic information from the intact copy allows high-fidelity repair of the DSB. In complex genomes rich in repetitive DNA sequences, HR is restricted to S and G2 phase of the ce...

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“…The two switch regions involved in CSR do not share any extensive homology, and switch junctions do not reveal any consensus sequence motif. This type of DNA recombination event can be best described as regionally specific recombination (19,39).When switch regions are transcribed in vitro, the RNA transcripts stay bound to the DNA template, forming an RNA-DNA hybrid (9,29,34,37). Biochemical probing has provided evidence that the RNA-DNA hybrid forms in vivo in switch regions and is most consistent with an R-loop structure (37).…”

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confidence: 99%

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Fine-Structure Analysis of Activation-Induced Deaminase Accessibility to Class Switch Region R-Loops

Roy

Bayramyan

et al. 2005

Molecular and Cellular Biology

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Activation-induced deaminase (AID) is essential for class switch recombination and somatic hypermutation, and it has the ability to deaminate single-stranded DNA at cytidines. Mammalian class switch regions form R-loops upon transcription in the physiological orientation. The displaced DNA strand of an R-loop is forced to wrap around the RNA-DNA hybrid; hence, it may not have complete exposure to proteins. A fundamental question concerns the extent to which AID is accessible to the displaced strand of a transcription-generated R-loop. We used a minimal R-loop to carry out high-resolution analysis of the precise locations of AID action. We found that AID deaminates on the displaced DNA strand across the entire length of the R-loop. Displaced strand locations with a WRC (where W is A or T and R is A or G) sequence are preferred targets, but there are clear exceptions. These WRC deviations may be due to steric constraints on the accessibility of AID to these sites as the displaced strand twists around the RNA-DNA duplex. This phenomenon may explain the lack of WRC site preference at the mutations surrounding class switch recombination junctions.Class switch recombination (CSR) is a DNA recombinational event that occurs in germinal-center B cells (6,14,39). By undergoing class switch recombination, mature B cells can switch their immunoglobulin heavy-chain constant regions from (which encodes the IgM subtype) to other heavy-chain isotypes (␥ for IgG, ␣ for IgA, and ⑀ for IgE, respectively). Class switch recombination is mediated by large (2-to 12-kb) repetitive regions, called switch regions, upstream of each coding constant-region exon (14). Recombination is thought to occur through a DNA double-strand break (DSB) intermediate (25). CSR generates DSBs that can be detected by ligationmediated PCR (4, 30, 36); moreover, the deleted intervening DNA between the two breaks forms a circular molecule (17,18,22,35), which is also detectable in class-switching B cells. The joining of the two chromosomal ends of the DSB is thought to be mediated by the nonhomologous DNA endjoining pathway (3,6,20,21), although dependence on some components is not certain (1).A key step in committing a certain switch region to recombination is transcription through that switch region from an upstream promoter (called an I exon promoter) (39). These transcripts are called germ line transcripts [to be distinguished from the transcript containing the V(D)J exon] or sterile transcripts, because they do not encode any protein (14, 39). The germ line transcripts are highly G rich, due to an asymmetry between a G-rich nontemplate and a C-rich template DNA strand of the switch region. The two switch regions involved in CSR do not share any extensive homology, and switch junctions do not reveal any consensus sequence motif. This type of DNA recombination event can be best described as regionally specific recombination (19,39).When switch regions are transcribed in vitro, the RNA transcripts stay bound to the DNA template, forming an RNA-DNA hybrid (9,...

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Site‐specific recombination in the immune system ¹

Cited by 162 publications

References 52 publications

A murine retrovirus induces proliferation of unique lymphoid cell lines expressing T-cell-receptor structures utilizing common variable region alpha and beta chain genes.

A murine retrovirus induces proliferation of unique lymphoid cell lines expressing T-cell-receptor structures utilizing common variable region alpha and beta chain genes.

X-ray repair cross-complementing protein 1 (XRCC1) deficiency enhances class switch recombination and is permissive for alternative end joining

Fine-Structure Analysis of Activation-Induced Deaminase Accessibility to Class Switch Region R-Loops

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Site‐specific recombination in the immune system 1

Cited by 162 publications

References 52 publications

A murine retrovirus induces proliferation of unique lymphoid cell lines expressing T-cell-receptor structures utilizing common variable region alpha and beta chain genes.

A murine retrovirus induces proliferation of unique lymphoid cell lines expressing T-cell-receptor structures utilizing common variable region alpha and beta chain genes.

X-ray repair cross-complementing protein 1 (XRCC1) deficiency enhances class switch recombination and is permissive for alternative end joining

Fine-Structure Analysis of Activation-Induced Deaminase Accessibility to Class Switch Region R-Loops

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Site‐specific recombination in the immune system ¹