Integrated signaling in developing lymphocytes

Bednarski, Jeffrey J.; Sleckman, Barry P.

doi:10.4161/cc.22021

Cited by 13 publications

(8 citation statements)

References 77 publications

(117 reference statements)

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“…RAG-induced DSBs activate the ATM kinase, which aids in efficient DSB repair (57). ATM recently was shown to help enforce allelic exclusion at Igk loci by downregulating Rag1 and Rag2 transcription in response to a RAG-induced DSB (58).…”

Section: Discussionmentioning

confidence: 99%

Peripheral subnuclear positioning suppresses Tcrb recombination and segregates Tcrb alleles from RAG2

Chan¹,

Teng²,

Corbett³

et al. 2013

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

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Allelic exclusion requires that the two alleles at antigen-receptor loci attempt to recombine variable (V), diversity (D), and joining (J) gene segments [V(D)J recombination] asynchronously in nuclei of developing lymphocytes. It previously was shown that T-cell receptor β (Tcrb) alleles frequently and stochastically associate with the nuclear lamina and pericentromeric heterochromatin in CD4 − CD8− thymocytes. Moreover, rearranged alleles were underrepresented at these locations. Here we used 3D immunofluorescence in situ hybridization to identify recently rearranged Tcrb alleles based on the accumulation of the DNA-repair protein 53BP1. We found that Tcrb alleles recombine asynchronously in double-negative thymocytes and that V(D)J recombination is suppressed on peripheral as compared with central Tcrb alleles. Moreover, the recombination events that did take place at the nuclear periphery preferentially occurred on Tcrb alleles that were partially dissociated from the nuclear lamina. To understand better the mechanism by which V(D)J recombination is suppressed at the nuclear periphery, we evaluated the subnuclear distribution of recombination-activating gene 2 (RAG2) protein. We found that RAG2 abundance was reduced at the nuclear periphery. Moreover, RAG2 was distributed differently from RNA polymerase II and histone H3K4 trimethylation. Our data suggest that the nuclear periphery suppresses V(D)J recombination, at least in part, by segregating Tcrb alleles from RAG proteins.T-cell development | thymus A ntigen receptor variable (V), diversity (D), and joining (J) gene segments are assembled by V(D)J recombination in immature T and B lymphocytes to generate diverse repertoires of T-cell receptors (TCRs) and B-cell receptors (BCRs), respectively (1). V(D)J recombination is initiated by the recombination-activating gene (RAG) 1 and 2 proteins, which bind to and induce double-strand breaks (DSBs) at recombination signal sequences that flank V, D, and J segments. V(D)J recombination at antigen-receptor loci is regulated according to cell lineage and developmental stage (2). In addition, at some loci V (D)J recombination is regulated to enforce allelic exclusion, so that a complete antigen-receptor protein is produced by only one allele (3, 4). However, the mechanisms that establish allelic exclusion are poorly understood.Among TCR loci, only the T-cell receptor β (Tcrb) locus is allelically excluded (5). Tcrb recombination occurs in CD4 − CD8 − double-negative (DN) thymocytes and is ordered, beginning with D β -J β rearrangement, which can occur on both alleles. Allelic exclusion then is initiated by V β -to-DJ β recombination, which is thought to occur asynchronously, i.e., on one allele at a time. This asynchrony allows thymocytes time to test each allele for the creation of an ORF. TCRβ proteins are sensed by their assembly with pre-Tα and CD3 chains to create a pre-TCR signaling complex; pre-TCR signals then suppress further Tcrb recombination and promote thymocyte proliferation and differentiation to the CD...

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Section: Discussionmentioning

confidence: 99%

Peripheral subnuclear positioning suppresses Tcrb recombination and segregates Tcrb alleles from RAG2

Chan¹,

Teng²,

Corbett³

et al. 2013

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

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“…Located on chromosome 11q 22-23, it includes 66 exons with a 9168 base pair coding sequence, and encodes a PI3K-related serine/threonine protein kinase (PIKK) that helps maintain genomic integrity. ATM plays a central role in the repair of DNA double-strand breaks (DSB), which can be induced by ionizing radiation, chemotherapy drugs, or oxidative stress, or occur during normal physiologic events like meiotic recombination or rearrangement of antibody genes during B-cell maturation (8,9).…”

Section: Function and Structure Of Atmmentioning

confidence: 99%

ATM Mutations in Cancer: Therapeutic Implications

Choi¹,

Kipps²,

Kurzrock³

2016

Molecular Cancer Therapeutics

390

318

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Activation of checkpoint arrest and homologous DNA repair are necessary for maintenance of genomic integrity during DNA replication. Germ-line mutations of the ataxia telangiectasia mutated (ATM) gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Somatic ATM mutations or deletions are commonly found in lymphoid malignancies, as well as a variety of solid tumors. Such mutations may result in chemotherapy resistance and adverse prognosis, but may also be exploited by existing or emerging targeted therapies that produce synthetic lethal states.

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“…Following DNA cleavage, RAG stabilizes the four broken DNA ends in a postcleavage complex that directs repair by the ubiquitous classical NHEJ pathway . In response to DNA DSBs, PI3K‐like Ser/Thr kinases ataxia‐telangiectasia mutated (ATM) kinase and DNA‐dependent protein kinase (DNA‐PK), which phosphorylate hundreds of targets necessary for the downstream activation of DDR pathways and the initiation of apoptosis in cells that fail to repair DNA breaks . Specifically, ATM phosphorylates the CHK2 kinase leading to the phosphorylation of Cdc25a promoting cell‐cycle arrest and apoptosis .…”

Section: Canonical Role Of Rag Proteins In Adaptive Lymphocytesmentioning

confidence: 99%

“…Some of the underlying molecular mechanisms that control NK‐cell function and longevity, resulting in effector and memory NK cells subsets during pathogen challenge, have only recently come to light. DNA damage is generally assumed to be a detrimental event, frequently associated with impaired cell survival or cellular transformation . However, a growing body of evidence suggests that focal DNA breaks are a mechanism for normal cell development, differentiation, and function.…”

Section: Introductionmentioning

confidence: 99%

Novel molecular mechanism for generating NK‐cell fitness and memory

Karo

Sun

2015

Eur J Immunol

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The mammalian immune system has been traditionally subdivided into two compartments known as the innate and the adaptive. T cells and B cells, which rearrange their antigen receptor genes using the RAG recombinase, comprise the adaptive arm of immunity. Meanwhile, every other white blood cell has been grouped together under the broad umbrella of innate immunity, including natural killer (NK) cells. NK cells are considered innate lymphocytes because of their rapid responses to stressed cells and their ability to develop without receptor gene rearrangement (i.e. in RAG-deficient mice). However, new findings implicate a critical function for RAG proteins during NK cell ontogeny, and suggest a novel mechanism by which controlled DNA breaks during NK cell development dictate the fitness, function, and longevity of these cells. This review highlights recent work describing how DNA break events can impact cellular differentiation and fitness in a variety of cell types and settings.

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Integrated signaling in developing lymphocytes

Cited by 13 publications

References 77 publications

Peripheral subnuclear positioning suppresses Tcrb recombination and segregates Tcrb alleles from RAG2

Peripheral subnuclear positioning suppresses Tcrb recombination and segregates Tcrb alleles from RAG2

ATM Mutations in Cancer: Therapeutic Implications

Novel molecular mechanism for generating NK‐cell fitness and memory

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