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Barry P. Sleckman - One of the best experts on this subject based on the ideXlab platform.
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At the intersection of DNA damage and immune responses
Nature Reviews Immunology, 2019Co-Authors: Jeffrey J Bednarski, Barry P. SleckmanAbstract:Double-strand breaks in DNA generated during the normal assembly and diversification of Lymphocyte Antigen Receptor genes or by genotoxic agents during infection activate DNA damage responses. Besides repairing damaged DNA, these responses trigger important signalling events that regulate immune cell development and function. DNA damage occurs on exposure to genotoxic agents and during physiological DNA transactions. DNA double-strand breaks (DSBs) are particularly dangerous lesions that activate DNA damage response (DDR) kinases, leading to initiation of a canonical DDR (cDDR). This response includes activation of cell cycle checkpoints and engagement of pathways that repair the DNA DSBs to maintain genomic integrity. In adaptive immune cells, programmed DNA DSBs are generated at precise genomic locations during the assembly and diversification of Lymphocyte Antigen Receptor genes. In innate immune cells, the production of genotoxic agents, such as reactive nitrogen molecules, in response to pathogens can also cause genomic DNA DSBs. These DSBs in adaptive and innate immune cells activate the cDDR. However, recent studies have demonstrated that they also activate non-canonical DDRs (ncDDRs) that regulate cell type-specific processes that are important for innate and adaptive immune responses. Here, we review these ncDDRs and discuss how they integrate with other signals during immune system development and function.
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aberrantly resolved rag mediated dna breaks in atm deficient Lymphocytes target chromosomal breakpoints in cis
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Grace K Mahowald, Andrea L Bredemeyer, Craig H Bassing, Jason M Baron, Michael A Mahowald, Shashikant Kulkarni, Barry P. SleckmanAbstract:Canonical chromosomal translocations juxtaposing Antigen Receptor genes and oncogenes are a hallmark of many lymphoid malignancies. These translocations frequently form through the joining of DNA ends from double-strand breaks (DSBs) generated by the recombinase activating gene (RAG)-1 and -2 proteins at Lymphocyte Antigen Receptor loci and breakpoint targets near oncogenes. Our understanding of chromosomal breakpoint target selection comes primarily from the analyses of these lesions, which are selected based on their transforming properties. RAG DSBs are rarely resolved aberrantly in wild-type developing Lymphocytes. However, in ataxia telangiectasia mutated (ATM)-deficient Lymphocytes, RAG breaks are frequently joined aberrantly, forming chromosomal lesions such as translocations that predispose (ATM)-deficient mice and humans to the development of lymphoid malignancies. Here, an approach that minimizes selection biases is used to isolate a large cohort of breakpoint targets of aberrantly resolved RAG DSBs in Atm-deficient Lymphocytes. Analyses of this cohort revealed that frequently, the breakpoint targets for aberrantly resolved RAG breaks are other DSBs. Moreover, these nonselected lesions exhibit a bias for using breakpoints in cis, forming small chromosomal deletions, rather than breakpoints in trans, forming chromosomal translocations.
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mrn complex function in the repair of chromosomal rag mediated dna double strand breaks
Journal of Experimental Medicine, 2009Co-Authors: Beth A. Helmink, Andrea L Bredemeyer, Girdhar G. Sharma, Ching-yu Huang, Laura M Walker, Tej K. Pandita, Craig H Bassing, Jeffrey J Bednarski, Barry P. SleckmanAbstract:The Mre11–Rad50–Nbs1 (MRN) complex functions in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) at postreplicative stages of the cell cycle. During HR, the MRN complex functions directly in the repair of DNA DSBs and in the initiation of DSB responses through activation of the ataxia telangiectasia-mutated (ATM) serine-threonine kinase. Whether MRN functions in DNA damage responses before DNA replication in G0/G1 phase cells has been less clear. In developing G1-phase Lymphocytes, DNA DSBs are generated by the Rag endonuclease and repaired during the assembly of Antigen Receptor genes by the process of V(D)J recombination. Mice and humans deficient in MRN function exhibit lymphoid phenotypes that are suggestive of defects in V(D)J recombination. We show that during V(D)J recombination, MRN deficiency leads to the aberrant joining of Rag DSBs and to the accumulation of unrepaired coding ends, thus establishing a functional role for MRN in the repair of Rag-mediated DNA DSBs. Moreover, these defects in V(D)J recombination are remarkably similar to those observed in ATM-deficient Lymphocytes, suggesting that ATM and MRN function in the same DNA DSB response pathways during Lymphocyte Antigen Receptor gene assembly.
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Lymphocyte Antigen Receptor gene assembly: multiple layers of regulation.
Immunologic Research, 2005Co-Authors: Barry P. SleckmanAbstract:Lymphocyte Antigen Receptor genes are assembled through the cutting and joining of segments of DNA in developing Lymphocytes. The basic features of the biochemical steps of this assembly process, referred to as the V(D)J recombination, are similar for the assembly of all Lymphocyte Antigen Receptor genes, yet this assembly is precisely regulated in several important contexts during Lymphocyte development. It has long been appreciated that this occurs through modulation of accessibility of Antigen Receptor loci to the enzymatic complex that assembles Antigen Receptor genes. However, recent studies have suggested that some regulatory constraints may be enforced at the level of the V(D)J recombination reaction itself. This review focuses on recent advances in the understanding of the regulation of Antigen Receptor gene assembly, with particular attention paid to the assembly of T-cell Receptor β-chain genes during T-cell development.
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Lymphocyte Antigen Receptor gene assembly: multiple layers of regulation.
Immunologic Research, 2005Co-Authors: Barry P. SleckmanAbstract:Lymphocyte Antigen Receptor genes are assembled through the cutting and joining of segments of DNA in developing Lymphocytes. The basic features of the biochemical steps of this assembly process, referred to as the V(D)J recombination, are similar for the assembly of all Lymphocyte Antigen Receptor genes, yet this assembly is precisely regulated in several important contexts during Lymphocyte development. It has long been appreciated that this occurs through modulation of accessibility of Antigen Receptor loci to the enzymatic complex that assembles Antigen Receptor genes. However, recent studies have suggested that some regulatory constraints may be enforced at the level of the V(D)J recombination reaction itself. This review focuses on recent advances in the understanding of the regulation of Antigen Receptor gene assembly, with particular attention paid to the assembly of T-cell Receptor beta-chain genes during T-cell development.
Anthony L Defranco - One of the best experts on this subject based on the ideXlab platform.
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targets of b Lymphocyte Antigen Receptor signal transduction include the p21ras gtpase activating protein gap and two gap associated proteins
Journal of Immunology, 1993Co-Authors: Michael R Gold, Mary T Crowley, G A Martin, F Mccormick, Anthony L DefrancoAbstract:Cross-linking membrane Ig (mIg) on B cells stimulates tyrosine phosphorylation of proteins involved in signal transduction including the mIg-associated proteins Ig-alpha and Ig-beta, the tyrosine kinases p53/p56lyn, p55blk, p59fyn, and PTK72, phosphatidylinositol 3-kinase, phospholipase C gamma 1 and gamma 2, and the mitogen-activated protein kinase. We now show that the p21ras GTPase-activating protein (GAP) is also a substrate for mIg-activated tyrosine kinases. p21ras is a key regulator of cell growth and GAP may act as both a regulator of p21ras activity and as a downstream effector of p21ras. We found that mIg cross-linking caused a rapid increase in tyrosine phosphorylation of GAP in the immature B cell line WEHI-231, the mature B cell lines BAL 17 and Daudi, and the IgG-bearing B cell line A20. In fibroblasts, tyrosine kinase activation causes GAP to associate with two other tyrosine-phosphorylated proteins, p62 and p190, which have homologies to an RNA-binding protein and a transcriptional repressor, respectively. Similarly, mlg cross-linking induced the association of GAP with a 62-kDa tyrosine-phosphorylated protein in BAL 17, WEHI-231, and Daudi cells. Anti-Ig treatment also increased the amount of a 190-kDa tyrosine-phosphorylated protein associated with GAP in WEHI-231 and Daudi cells. After separation by SDS-PAGE and transfer to nitrocellulose, the tyrosine-phosphorylated p62 and p190 present in anti-GAP immunoprecipitates from B cells were capable of binding radiolabeled recombinant GAP, as previously reported for the GAP-associated p62 and p190 from fibroblasts. The amount of p62 that could be detected in this way after immunoprecipitation with antiphosphotyrosine antibodies was much greater from anti-IgM-treated BAL 17 cells than from unstimulated BAL 17 cells. This probably reflects anti-Ig-induced tyrosine phosphorylation of p62. In any case, GAP, p62, and/or p190 may be involved in signal transduction by mIg in B cells.
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Tyrosine phosphorylation and the mechanism of signal transduction by the B-Lymphocyte Antigen Receptor.
European Journal of Biochemistry, 1992Co-Authors: Anthony L DefrancoAbstract:In the 1950s, Burnet developed the theory of clonal selection to explain the specificity of antibody responses. He postulated that each antibody-producing cell makes antibody molecules with a single specificity, and, moreover, that it makes these antibodies in two forms, a secreted form and a cell-surface form, the latter of which serves as an Antigen Receptor. According to this theory, Antigen binding to cell-surface Ig leads to proliferation of Antigen-binding cells. Following clonal expansion, a significant proportion of these cells would initiate high-level antibody production, whereas other cells would become memory B cells and be reserved for the secondary immune response observed upon return of the Antigen.
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stimulation of protein tyrosine phosphorylation by the b Lymphocyte Antigen Receptor
Nature, 1990Co-Authors: Michael R Gold, Anthony L DefrancoAbstract:SIGNALLING by membrane immunoglobulin, the B-Lymphocyte Antigen Receptor, regulates B-cell maturation and activation. Crosslinking of membrane immunoglobulin by Antigen or by anti-immunoglobulin antibodies inactivates immature B cells, eliminating many of the B cells capable of producing auto-antibodies1. By contrast, crosslinking of membrane immunoglobulin promotes activation of mature B cells for clonal expansion and antibody production against foreign Antigens2. Crosslinking membrane IgM on the immature B-cell line WEHI-231 induces growth arrest3. This response may be analogous to the deletion or inactivation of immature B cells that is induced by Antigen or anti-IgM antibodies. Membrane immunoglobulin crosslinking stimulates phosphoinosi-tide hydrolysis, which leads to increases in intracellular calcium and activation of protein kinase C4–6. The induced phosphoinositide breakdown is important for inhibiting WEHI-231 growth (ref. 7 and D. Page, M.R.G., K. Fahey, L. Matsuuchi and A.L.D., manuscript submitted for publication), but may not be sufficient, as agents that elevate calcium and activate protein kinase C cause only partial growth arrest7. We now show that in both mature splenic B cells and the immature B–cell line WEHI-231 crosslinking membrane immunoglobulin also stimulates phosphorylation of protein tyrosine, a reaction that has been implicated as a key regulator of cell growth. Most of these phosphorylations were not a consequence of the phosphoinositide pathway. Thus, tyrosine phosphorylation is a second mode of transmembrane signalling by membrane immunoglobulin.
Craig H Bassing - One of the best experts on this subject based on the ideXlab platform.
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Poor Quality Vβ Recombination Signal Sequences Enforce TCRβ Allelic Exclusion by Limiting the Frequency of Vβ Recombination
bioRxiv, 2020Co-Authors: Katherine S. Yang-iott, Craig H. Bassing, Katharina E. Hayer, Kyutae D. Lee, Morgann A. Reed, Craig H BassingAbstract:Monoallelic expression (allelic exclusion) of T and B Lymphocyte Antigen Receptor genes is achieved by the assembly of a functional gene through V(D)J recombination on one allele and subsequent feedback inhibition of recombination on the other allele. There has been no validated mechanism for how only one allele of any Antigen Receptor locus assembles a functional gene prior to feedback inhibition. Here, we demonstrate that replacement of a single V{beta} recombination signal sequence (RSS) with a better RSS increases V{beta} rearrangement, reveals Tcrb alleles compete for utilization in the {beta} T cell Receptor (TCR) repertoire, and elevates the fraction of {beta} T cells expressing TCR{beta} protein from both alleles. The data indicate that poor qualities of V{beta} RSSs for recombination with D{beta} and J{beta} RSSs enforces allelic exclusion by stochastically limiting the incidence of functional V{beta} rearrangements on both alleles before feedback inhibition terminates V{beta} recombination.
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ataxia telangiectasia mutated atm and dna pkcs kinases have overlapping activities during chromosomal signal joint formation
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Eric J Gapud, Andrea L Bredemeyer, Laura M Walker, Craig H Bassing, Jeffrey J Bednarski, Yair Dorsett, Elsa Callen, Grace K Mahowald, Peter J Mckinnon, Andre NussenzweigAbstract:Lymphocyte Antigen Receptor gene assembly occurs through the process of V(D)J recombination, which is initiated when the RAG endonuclease introduces DNA DSBs at two recombining gene segments to form broken DNA coding end pairs and signal end pairs. These paired DNA ends are joined by proteins of the nonhomologous end-joining (NHEJ) pathway of DSB repair to form a coding joint and signal joint, respectively. RAG DSBs are generated in G1-phase developing Lymphocytes, where they activate the ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases to orchestrate diverse cellular DNA damage responses including DSB repair. Paradoxically, although Atm and DNA-PKcs both function during coding joint formation, Atm appears to be dispensible for signal joint formation; and although some studies have revealed an activity for DNA-PKcs during signal joint formation, others have not. Here we show that Atm and DNA-PKcs have overlapping catalytic activities that are required for chromosomal signal joint formation and for preventing the aberrant resolution of signal ends as potentially oncogenic chromosomal translocations.
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aberrantly resolved rag mediated dna breaks in atm deficient Lymphocytes target chromosomal breakpoints in cis
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Grace K Mahowald, Andrea L Bredemeyer, Craig H Bassing, Jason M Baron, Michael A Mahowald, Shashikant Kulkarni, Barry P. SleckmanAbstract:Canonical chromosomal translocations juxtaposing Antigen Receptor genes and oncogenes are a hallmark of many lymphoid malignancies. These translocations frequently form through the joining of DNA ends from double-strand breaks (DSBs) generated by the recombinase activating gene (RAG)-1 and -2 proteins at Lymphocyte Antigen Receptor loci and breakpoint targets near oncogenes. Our understanding of chromosomal breakpoint target selection comes primarily from the analyses of these lesions, which are selected based on their transforming properties. RAG DSBs are rarely resolved aberrantly in wild-type developing Lymphocytes. However, in ataxia telangiectasia mutated (ATM)-deficient Lymphocytes, RAG breaks are frequently joined aberrantly, forming chromosomal lesions such as translocations that predispose (ATM)-deficient mice and humans to the development of lymphoid malignancies. Here, an approach that minimizes selection biases is used to isolate a large cohort of breakpoint targets of aberrantly resolved RAG DSBs in Atm-deficient Lymphocytes. Analyses of this cohort revealed that frequently, the breakpoint targets for aberrantly resolved RAG breaks are other DSBs. Moreover, these nonselected lesions exhibit a bias for using breakpoints in cis, forming small chromosomal deletions, rather than breakpoints in trans, forming chromosomal translocations.
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mrn complex function in the repair of chromosomal rag mediated dna double strand breaks
Journal of Experimental Medicine, 2009Co-Authors: Beth A. Helmink, Andrea L Bredemeyer, Girdhar G. Sharma, Ching-yu Huang, Laura M Walker, Tej K. Pandita, Craig H Bassing, Jeffrey J Bednarski, Barry P. SleckmanAbstract:The Mre11–Rad50–Nbs1 (MRN) complex functions in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) at postreplicative stages of the cell cycle. During HR, the MRN complex functions directly in the repair of DNA DSBs and in the initiation of DSB responses through activation of the ataxia telangiectasia-mutated (ATM) serine-threonine kinase. Whether MRN functions in DNA damage responses before DNA replication in G0/G1 phase cells has been less clear. In developing G1-phase Lymphocytes, DNA DSBs are generated by the Rag endonuclease and repaired during the assembly of Antigen Receptor genes by the process of V(D)J recombination. Mice and humans deficient in MRN function exhibit lymphoid phenotypes that are suggestive of defects in V(D)J recombination. We show that during V(D)J recombination, MRN deficiency leads to the aberrant joining of Rag DSBs and to the accumulation of unrepaired coding ends, thus establishing a functional role for MRN in the repair of Rag-mediated DNA DSBs. Moreover, these defects in V(D)J recombination are remarkably similar to those observed in ATM-deficient Lymphocytes, suggesting that ATM and MRN function in the same DNA DSB response pathways during Lymphocyte Antigen Receptor gene assembly.
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ATM stabilizes DNA double-strand-break complexes during V(D)J recombination.
Nature, 2006Co-Authors: Andrea L Bredemeyer, Girdhar G. Sharma, Ching-yu Huang, Beth A. Helmink, Laura M Walker, Katrina C. Khor, Beth Nuskey, Kathleen E. Sullivan, Tej K. Pandita, Craig H BassingAbstract:Examination of the role of the ATM protein in oncogenic chromosomal translocations in the disease ataxia telangiectasia finds that ATM is involved directly in stabilizing a complex that occurs when DNA double-strand breaks are made in Lymphocyte Antigen Receptor loci. When the complex is not stabilized, the DNA ends are able to undergo aberrant reactions that can lead to translocations. The ATM (ataxia-telangiectasia mutated) protein kinase mediates early cellular responses to DNA double-strand breaks (DSBs) generated during metabolic processes or by DNA-damaging agents1,2,3,4. ATM deficiency leads to ataxia-telangiectasia, a disease marked by lymphopenia, genomic instability and an increased predisposition to lymphoid malignancies with chromosomal translocations involving Lymphocyte Antigen Receptor loci5,6. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs1,2,3,4. However, defects in these pathways of the DNA damage response cannot fully account for the phenotypes of ATM deficiency. Here, we show that ATM also functions directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during Lymphocyte Antigen Receptor gene assembly. When coupled with the cell-cycle checkpoint and pro-apoptotic activities of ATM, these findings provide a molecular explanation for the increase in lymphoid tumours with translocations involving Antigen Receptor loci associated with ataxia-telangiectasia.
Andrea L Bredemeyer - One of the best experts on this subject based on the ideXlab platform.
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ataxia telangiectasia mutated atm and dna pkcs kinases have overlapping activities during chromosomal signal joint formation
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Eric J Gapud, Andrea L Bredemeyer, Laura M Walker, Craig H Bassing, Jeffrey J Bednarski, Yair Dorsett, Elsa Callen, Grace K Mahowald, Peter J Mckinnon, Andre NussenzweigAbstract:Lymphocyte Antigen Receptor gene assembly occurs through the process of V(D)J recombination, which is initiated when the RAG endonuclease introduces DNA DSBs at two recombining gene segments to form broken DNA coding end pairs and signal end pairs. These paired DNA ends are joined by proteins of the nonhomologous end-joining (NHEJ) pathway of DSB repair to form a coding joint and signal joint, respectively. RAG DSBs are generated in G1-phase developing Lymphocytes, where they activate the ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases to orchestrate diverse cellular DNA damage responses including DSB repair. Paradoxically, although Atm and DNA-PKcs both function during coding joint formation, Atm appears to be dispensible for signal joint formation; and although some studies have revealed an activity for DNA-PKcs during signal joint formation, others have not. Here we show that Atm and DNA-PKcs have overlapping catalytic activities that are required for chromosomal signal joint formation and for preventing the aberrant resolution of signal ends as potentially oncogenic chromosomal translocations.
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aberrantly resolved rag mediated dna breaks in atm deficient Lymphocytes target chromosomal breakpoints in cis
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Grace K Mahowald, Andrea L Bredemeyer, Craig H Bassing, Jason M Baron, Michael A Mahowald, Shashikant Kulkarni, Barry P. SleckmanAbstract:Canonical chromosomal translocations juxtaposing Antigen Receptor genes and oncogenes are a hallmark of many lymphoid malignancies. These translocations frequently form through the joining of DNA ends from double-strand breaks (DSBs) generated by the recombinase activating gene (RAG)-1 and -2 proteins at Lymphocyte Antigen Receptor loci and breakpoint targets near oncogenes. Our understanding of chromosomal breakpoint target selection comes primarily from the analyses of these lesions, which are selected based on their transforming properties. RAG DSBs are rarely resolved aberrantly in wild-type developing Lymphocytes. However, in ataxia telangiectasia mutated (ATM)-deficient Lymphocytes, RAG breaks are frequently joined aberrantly, forming chromosomal lesions such as translocations that predispose (ATM)-deficient mice and humans to the development of lymphoid malignancies. Here, an approach that minimizes selection biases is used to isolate a large cohort of breakpoint targets of aberrantly resolved RAG DSBs in Atm-deficient Lymphocytes. Analyses of this cohort revealed that frequently, the breakpoint targets for aberrantly resolved RAG breaks are other DSBs. Moreover, these nonselected lesions exhibit a bias for using breakpoints in cis, forming small chromosomal deletions, rather than breakpoints in trans, forming chromosomal translocations.
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mrn complex function in the repair of chromosomal rag mediated dna double strand breaks
Journal of Experimental Medicine, 2009Co-Authors: Beth A. Helmink, Andrea L Bredemeyer, Girdhar G. Sharma, Ching-yu Huang, Laura M Walker, Tej K. Pandita, Craig H Bassing, Jeffrey J Bednarski, Barry P. SleckmanAbstract:The Mre11–Rad50–Nbs1 (MRN) complex functions in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) at postreplicative stages of the cell cycle. During HR, the MRN complex functions directly in the repair of DNA DSBs and in the initiation of DSB responses through activation of the ataxia telangiectasia-mutated (ATM) serine-threonine kinase. Whether MRN functions in DNA damage responses before DNA replication in G0/G1 phase cells has been less clear. In developing G1-phase Lymphocytes, DNA DSBs are generated by the Rag endonuclease and repaired during the assembly of Antigen Receptor genes by the process of V(D)J recombination. Mice and humans deficient in MRN function exhibit lymphoid phenotypes that are suggestive of defects in V(D)J recombination. We show that during V(D)J recombination, MRN deficiency leads to the aberrant joining of Rag DSBs and to the accumulation of unrepaired coding ends, thus establishing a functional role for MRN in the repair of Rag-mediated DNA DSBs. Moreover, these defects in V(D)J recombination are remarkably similar to those observed in ATM-deficient Lymphocytes, suggesting that ATM and MRN function in the same DNA DSB response pathways during Lymphocyte Antigen Receptor gene assembly.
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ATM stabilizes DNA double-strand-break complexes during V(D)J recombination.
Nature, 2006Co-Authors: Andrea L Bredemeyer, Girdhar G. Sharma, Ching-yu Huang, Beth A. Helmink, Laura M Walker, Katrina C. Khor, Beth Nuskey, Kathleen E. Sullivan, Tej K. Pandita, Craig H BassingAbstract:Examination of the role of the ATM protein in oncogenic chromosomal translocations in the disease ataxia telangiectasia finds that ATM is involved directly in stabilizing a complex that occurs when DNA double-strand breaks are made in Lymphocyte Antigen Receptor loci. When the complex is not stabilized, the DNA ends are able to undergo aberrant reactions that can lead to translocations. The ATM (ataxia-telangiectasia mutated) protein kinase mediates early cellular responses to DNA double-strand breaks (DSBs) generated during metabolic processes or by DNA-damaging agents1,2,3,4. ATM deficiency leads to ataxia-telangiectasia, a disease marked by lymphopenia, genomic instability and an increased predisposition to lymphoid malignancies with chromosomal translocations involving Lymphocyte Antigen Receptor loci5,6. ATM activates cell-cycle checkpoints and can induce apoptosis in response to DNA DSBs1,2,3,4. However, defects in these pathways of the DNA damage response cannot fully account for the phenotypes of ATM deficiency. Here, we show that ATM also functions directly in the repair of chromosomal DNA DSBs by maintaining DNA ends in repair complexes generated during Lymphocyte Antigen Receptor gene assembly. When coupled with the cell-cycle checkpoint and pro-apoptotic activities of ATM, these findings provide a molecular explanation for the increase in lymphoid tumours with translocations involving Antigen Receptor loci associated with ataxia-telangiectasia.
Jeffrey J Bednarski - One of the best experts on this subject based on the ideXlab platform.
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At the intersection of DNA damage and immune responses
Nature Reviews Immunology, 2019Co-Authors: Jeffrey J Bednarski, Barry P. SleckmanAbstract:Double-strand breaks in DNA generated during the normal assembly and diversification of Lymphocyte Antigen Receptor genes or by genotoxic agents during infection activate DNA damage responses. Besides repairing damaged DNA, these responses trigger important signalling events that regulate immune cell development and function. DNA damage occurs on exposure to genotoxic agents and during physiological DNA transactions. DNA double-strand breaks (DSBs) are particularly dangerous lesions that activate DNA damage response (DDR) kinases, leading to initiation of a canonical DDR (cDDR). This response includes activation of cell cycle checkpoints and engagement of pathways that repair the DNA DSBs to maintain genomic integrity. In adaptive immune cells, programmed DNA DSBs are generated at precise genomic locations during the assembly and diversification of Lymphocyte Antigen Receptor genes. In innate immune cells, the production of genotoxic agents, such as reactive nitrogen molecules, in response to pathogens can also cause genomic DNA DSBs. These DSBs in adaptive and innate immune cells activate the cDDR. However, recent studies have demonstrated that they also activate non-canonical DDRs (ncDDRs) that regulate cell type-specific processes that are important for innate and adaptive immune responses. Here, we review these ncDDRs and discuss how they integrate with other signals during immune system development and function.
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ataxia telangiectasia mutated atm and dna pkcs kinases have overlapping activities during chromosomal signal joint formation
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Eric J Gapud, Andrea L Bredemeyer, Laura M Walker, Craig H Bassing, Jeffrey J Bednarski, Yair Dorsett, Elsa Callen, Grace K Mahowald, Peter J Mckinnon, Andre NussenzweigAbstract:Lymphocyte Antigen Receptor gene assembly occurs through the process of V(D)J recombination, which is initiated when the RAG endonuclease introduces DNA DSBs at two recombining gene segments to form broken DNA coding end pairs and signal end pairs. These paired DNA ends are joined by proteins of the nonhomologous end-joining (NHEJ) pathway of DSB repair to form a coding joint and signal joint, respectively. RAG DSBs are generated in G1-phase developing Lymphocytes, where they activate the ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases to orchestrate diverse cellular DNA damage responses including DSB repair. Paradoxically, although Atm and DNA-PKcs both function during coding joint formation, Atm appears to be dispensible for signal joint formation; and although some studies have revealed an activity for DNA-PKcs during signal joint formation, others have not. Here we show that Atm and DNA-PKcs have overlapping catalytic activities that are required for chromosomal signal joint formation and for preventing the aberrant resolution of signal ends as potentially oncogenic chromosomal translocations.
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mrn complex function in the repair of chromosomal rag mediated dna double strand breaks
Journal of Experimental Medicine, 2009Co-Authors: Beth A. Helmink, Andrea L Bredemeyer, Girdhar G. Sharma, Ching-yu Huang, Laura M Walker, Tej K. Pandita, Craig H Bassing, Jeffrey J Bednarski, Barry P. SleckmanAbstract:The Mre11–Rad50–Nbs1 (MRN) complex functions in the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) at postreplicative stages of the cell cycle. During HR, the MRN complex functions directly in the repair of DNA DSBs and in the initiation of DSB responses through activation of the ataxia telangiectasia-mutated (ATM) serine-threonine kinase. Whether MRN functions in DNA damage responses before DNA replication in G0/G1 phase cells has been less clear. In developing G1-phase Lymphocytes, DNA DSBs are generated by the Rag endonuclease and repaired during the assembly of Antigen Receptor genes by the process of V(D)J recombination. Mice and humans deficient in MRN function exhibit lymphoid phenotypes that are suggestive of defects in V(D)J recombination. We show that during V(D)J recombination, MRN deficiency leads to the aberrant joining of Rag DSBs and to the accumulation of unrepaired coding ends, thus establishing a functional role for MRN in the repair of Rag-mediated DNA DSBs. Moreover, these defects in V(D)J recombination are remarkably similar to those observed in ATM-deficient Lymphocytes, suggesting that ATM and MRN function in the same DNA DSB response pathways during Lymphocyte Antigen Receptor gene assembly.
