RAG-induced DNA double-strand breaks signal through Pim2 to promote pre–B cell survival and limit proliferation

Bednarski, Jeffrey J.; Nickless, Andrew; Bhattacharya, Deepta; Amin, Rupesh H.; Schlissel, Mark S.; Sleckman, Barry P.

doi:10.1084/jem.20112078

Cited by 48 publications

(104 citation statements)

References 26 publications

(49 reference statements)

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“…For isotype controls, an antibody recognizing the macrophage-specific protein MAC1 was used (eBiosciences 11-0112-81). For carboxyfluorescein succinimidyl ester (CFSE) loading experiments, CD19 + B-lineage cells were isolated from bone marrow using MACs microbeads (130-052-201), pulsed with 10 μM CSFE per the manufacturer's instructions (CellTrace CFSE; Life Technologies), and grown in 5 ng/mL IL-7 for 4 d. DNA content analysis was performed on these cultured cells as described previously (35).…”

Section: Molecular Analysesmentioning

confidence: 99%

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The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes

Collins

Kyle

Egawa

et al. 2015

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

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Genome stability relies on epigenetic mechanisms that enforce repression of endogenous retroviruses (ERVs). Current evidence suggests that distinct chromatin-based mechanisms repress ERVs in cells of embryonic origin (histone methylation dominant) vs. more differentiated cells (DNA methylation dominant). However, the latter aspect of this model has not been tested. Remarkably, and in contrast to the prevailing model, we find that repressive histone methylation catalyzed by the enzyme SETDB1 is critical for suppression of specific ERV families and exogenous retroviruses in committed B-lineage cells from adult mice. The profile of ERV activation in SETDB1-deficient B cells is distinct from that observed in corresponding embryonic tissues, despite the loss of repressive chromatin modifications at all ERVs. We provide evidence that, on loss of SETDB1, ERVs are activated in a lineage-specific manner depending on the set of transcription factors available to target proviral regulatory elements. These findings have important implications for genome stability in somatic cells, as well as the interface between epigenetic repression and viral latency.epigenetics | histone methylation | repression | transposable elements | retroviruses R epressive chromatin is a biochemical platform for many cellular processes (1), including gene silencing during development and the suppression of potentially mutagenic repetitive elements, such as endogenous retroviruses (ERVs). The formation and maintenance of repressive chromatin rely on epigenetic modification of its DNA and nucleosome components, including hypermethylation of CpG dinucleotides by DNA methyltransferases (DNMTs). DNA methylation patterns are conserved during replication, and this modification is thought to provide the most stable form of repression (1). An important modification for initiating repressive chromatin formation is trimethylation of histone H3 at the lysine 9 position (H3K9me3) by two major histone methyltransferases (HMTs). Suppressor Of Variegation 3-9 Homolog (SUV39H)1/2 complexes maintain this modification at constitutive heterochromatin and most long interspersed nuclear elements (LINEs), which together encompass the vast majority of H3K9me3 in chromatin (2, 3). In contrast, the HMT called SET Domain, Bifurcated 1 (SETDB1 a.k.a. ESET) is targeted primarily to ERVs, which must be silenced to maintain genome and transcriptome integrity (4).Long terminal repeat (LTR)-containing ERVs represent ∼10% of human and mouse genomes (5). Although most are defunct genomic artifacts, many species contain a substantial number of active ERVs (6). In mice, ERV expression is tissue and strain specific. The intracisternal A particle (IAP) and early transposon/ Mus musculus type D (ETn/MusD) families of ERVs are expressed predominantly in early embyronic tissues. One consequence of this de-repression is the acquisition of spontaneous germ-line mutations, with IAP and ETn retrotransposition accounting for nearly 15% of these genomic alterations in mice (5). Likewise, B lymph...

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Section: Molecular Analysesmentioning

confidence: 99%

“…Cloning of hairpin-MSCV-shRNA vectors containing shRNA sequences, production of retroviruses, and infection of pro-B cells has been described previously (35). The shPax5 targeting sequences were as follows: shPax5 1, 5′-CCAGCACTACTCTGACATCTTA-3′; shPax5, 2, 5′-ATACAATGATTCTTGGAGGTTA-3′.…”

Section: Molecular Analysesmentioning

confidence: 99%

The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes

Collins

Kyle

Egawa

et al. 2015

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

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“…Similar to genotoxic DSBs, in response to RAG DSBs, ATM phosphorylates the transcription factor p53, resulting in its stabilization and increased transcriptional activity. [31][32][33][34][35] Once activated, p53 regulates the expression of numerous cell cycle and cell death genes, including p21, PUMA, NOXA and BAX. 33,36 Deficiency of p53 results in a higher incidence of lymphoid malignancies with chromosomal translocations, consistent with an important role for this tumor suppressor in eliminating cells at risk for aberrant DNA repair and malignant transformation.…”

Section: Rag Dsbs Activate a Unique Transcriptional Programmentioning

confidence: 99%

“…31,42 The dual regulation of survival and cell death pathways by RAG DSBs is temporally balanced, allowing time for proper assembly of the antigen receptor genes, but ensuring elimination of cells with persistent DSBs at risk for errant repair. These opposing processes may enforce normal development and suppress malignant transformation.…”

Section: Rag Dsbs Activate a Unique Transcriptional Programmentioning

confidence: 99%

“…[46][47][48] The IL-7r also phosphorylates and activates the Akt (PKB) kinase, which cooperates with STAT5 signaling to support pre-B cell survival at least in part through phosphorylation and inactivation of the pro-apoptotic protein BAD. 10,31,49 Akt also phosphorylates the FoxO1 and FoxO3a transcription factors resulting in their cytoplasmic retention and inactivation. [50][51][52][53] Attenuation of IL-7 signals disables Akt and stabilizes the FoxO transcription factors, resulting in expression of RAG and activation of IgL gene rearrangement.…”

Section: Introductionmentioning

confidence: 99%

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Integrated signaling in developing lymphocytes

Bednarski

Sleckman

2012

Cell Cycle

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An overview of pim kinase as a target in multiple myeloma

et al. 2023

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Multiple myeloma (MM) is the second common hematologic malignancy manifesting as a clonal proliferation of plasma cells in the bone marrow. In recent years, high expression and activity of pim kinase have been found to be associated with both the progression and prognosis of a significant proportion of malignant diseases. Therefore, pim kinase has become a potential therapeutic target in the treatment of MM and some pim kinase inhibitors have demonstrated good efficacy in clinical trials. Based on nearly the entire literature searched from PubMed in the field of pim kinase in MM, the paper concluded how pim kinase got involved in the proliferation of myeloma cells, the progression of bone disease infiltration, and even in the regulation of the immune microenvironment. Next as a very promising drug, the effectiveness of pim kinase inhibitors as single agents or in combination with other drugs in the treatment of MM was also summarized. Our analysis will guide the clinical use of pim kinase inhibitors for managing tumor load and bone disease in MM patients.

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RAG-induced DNA double-strand breaks signal through Pim2 to promote pre–B cell survival and limit proliferation

Cited by 48 publications

References 26 publications

The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes

The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes

Integrated signaling in developing lymphocytes

An overview of pim kinase as a target in multiple myeloma

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