Inducible DNA breaks in Ig S regions are dependent on AID and UNG

Schrader, Carol E.; Linehan, Erin K.; Mochegova, Sofia N.; Woodland, Robert T.; Stavnezer, Janet

doi:10.1084/jem.20050872

Cited by 157 publications

(237 citation statements)

References 42 publications

(72 reference statements)

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“…Sex steroids suppress B lymphocyte production in murine bone marrow. Pre B-lymphocytes produce the heavy chain of IgM (μ chain) (58), under the influence of the IgM constant region gene (cμ) (59), which can act as a marker of pre-B cells. V(D)J recombination confers the ability of the immune system to respond to a vast number of foreign antigens, which occurs particularly in immature lymphocytes and is mediated by the recombination activating gene products Rag1 and Rag2 (60,61).…”

Section: Hematopoietic Stem Cellsmentioning

confidence: 99%

Sex Steroids and Stem Cell Function

Ray

Novotny

Crisostomo

et al. 2008

Mol Med

104

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Gender dimorphisms exist in the pathogenesis of a variety of cardiovascular, cardiopulmonary, neurodegenerative, and endocrine disorders. Estrogens exert immense influence on myocardial remodeling following ischemic insult, partially through paracrine growth hormone production by bone marrow mesenchymal stem cells (MSCs) and endothelial progenitor cells. Estrogens also facilitate the mobilization of endothelial progenitor cells to the ischemic myocardium and enhance neovascularization at the ischemic border zone. Moreover, estrogens limit pathological myocardial remodeling through the inhibitory effects on the proliferation of the cardiac fibroblasts. Androgens also may stimulate endothelial progenitor cell migration from the bone marrow, yet the larger role of androgens in disease pathogenesis is not well characterized. The beneficial effects of sex steroids include alteration of lipid metabolism in preadipocytes, modulation of bone metabolism and skeletal maturation, and prevention of osteoporosis through their effects on osteogenic precursors. In an example of sex steroid-specific effects, neural stem cells exhibit enhanced proliferation in response to estrogens, whereas androgens mediate inhibitory effects on their proliferation. Although stem cells can offer significant therapeutic benefits in various cardiovascular, neurodegenerative, endocrine disorders, and disorders of bone metabolism, a greater understanding of sex hormones on diverse stem cell populations is required to improve their ultimate clinical efficacy. In this review, we focus on the effects of estrogen and testosterone on various stem and progenitor cell types, and their relevant intracellular mechanisms.

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Section: Hematopoietic Stem Cellsmentioning

confidence: 99%

Sex Steroids and Stem Cell Function

Ray

Novotny

Crisostomo

et al. 2008

Mol Med

104

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“…Isotype switching is a dynamic process in B cells that is dependent on GLT and AID expression, DSB formation specific to S regions, and proliferation [2][3][4]20]. The earliest time that completed CSR has been detected is 72 h following stimulation [21,22].…”

Section: General Remarksmentioning

confidence: 99%

“…CSR is dependent on the expression of activation-induced deaminase (AID) and on expression of germ-line transcripts (GLT) through participating S regions (reviewed in [2]). AID-dependent double strand breaks (DSB) in S DNA are the initiating events for CSR [3][4][5][6]. To complete the switching process, recombination of the broken strands from two S regions occurs by nonhomologous end joining (reviewed in [2,7]).…”

Section: Introductionmentioning

confidence: 99%

NF‐κB binds to the immunoglobulin Sγ3 region in vivo during class switch recombination

2006

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Ig class switch recombination (CSR) is dependent upon the expression of activation-induced deaminase and targeted to specific isotypes by germ-line transcript expression and isotype-specific factors. NF-κB plays critical roles in multiple aspects of B cell biology and has been implicated in the mechanism of CSR by in vitro binding assays and altered S/S junctions derived from NF-κB p50-deficient mice. However, the pleiotropic contributions of NF-κB to gene expression in B cells has made discerning a direct role for NF-κB in CSR difficult. We now observe that binding of NF-κB components p50 and p65 is detected on Sγ3 in vivo following lipopolysaccharide (LPS) activation and repressed by LPS + IL-4, suggesting a direct role for this factor in CSR. In vivo footprinting confirms occupancy of a previously defined NF-κB recognition site in Sγ3 with the same temporal kinetics as found in the chromatin immunoprecipitation analysis. Binding of NF-κB components p50 and p65 was also detected on Sγ1 following B cell activation. H3 histone hyper acetylation at Sγ1 is strongly correlated with NF-κB binding, suggesting that NF-κB mediates chromatin remodeling in the Sγ3 and Sγ1 region.

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“…The main function of S regions appears to be the generation of double-strand breaks (DSBs) by serving as a target for activation-induced cytosine deaminase (AID) (5)(6)(7)(8). AID is essential for both SHM and CSR (9) and is believed to function by deaminating cytosine (C) to uracil (U) in DNA (10).…”

mentioning

confidence: 99%

Antisense transcripts from immunoglobulin heavy-chain locus V(D)J and switch regions

Perlot

Alt

2008

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

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Activation-induced cytosine deaminase (AID) is essential for both somatic hypermutation (SHM) and class switch recombination (CSR), two processes involved in antibody diversification. Previously, various groups showed both in vitro and in vivo that AID initiates SHM and CSR by deaminating cytosines in DNA in a transcription-dependent manner. Although in vivo both DNA strands are equally targeted by AID, many in vitro and bacterial experiments found that AID almost exclusively targets the nontemplate strand of a transcribed substrate. Here, we report the detection of antisense transcripts in assembled Ig heavy chain (IgH) variable region exons and their immediate downstream region, as well as in switch regions, sequences that, respectively, are targets for SHM and CSR in vivo. In contrast, we did not detect antisense transcripts from the C constant region exons, which lie between the IgH variable region exons and downstream S regions and which are not normally an AID target. Expression of the antisense variable region/flanking region and the S-region transcripts were found in all lymphocytes that transcribe these sequences in the sense direction. Steady-state levels of antisense transcripts appeared very low, and start sites potentially appeared heterogeneous. We discuss the potential implications of antisense IgH locus transcription for AID targeting or other processes.class switch recombination ͉ somatic hypermutation ͉ activation-induced cytosine deaminase ͉ bidirectional transcription

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Inducible DNA breaks in Ig S regions are dependent on AID and UNG

Cited by 157 publications

References 42 publications

Sex Steroids and Stem Cell Function

Sex Steroids and Stem Cell Function

NF‐κB binds to the immunoglobulin Sγ3 region in vivo during class switch recombination

Antisense transcripts from immunoglobulin heavy-chain locus V(D)J and switch regions

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