scholarly journals RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals

2016 ◽  
Vol 212 (4) ◽  
pp. 2124OIA21
Author(s):  
Jeffrey J. Bednarski ◽  
Ruchi Pandey ◽  
Emily Schulte ◽  
Lynn S. White ◽  
Bo-Ruei Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Double Strand Breaks ◽  
Cell Type ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
A Cell ◽  
Cell Type Specific

scholarly journals RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals

2016 ◽  
Vol 213 (2) ◽  
pp. 209-223 ◽  
Author(s):  
Jeffrey J. Bednarski ◽  
Ruchi Pandey ◽  
Emily Schulte ◽  
Lynn S. White ◽  
Bo-Ruei Chen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cell Cycle Checkpoint ◽  
Double Strand Breaks ◽  
Chain Gene ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

DNA double-strand breaks (DSBs) activate a canonical DNA damage response, including highly conserved cell cycle checkpoint pathways that prevent cells with DSBs from progressing through the cell cycle. In developing B cells, pre–B cell receptor (pre–BCR) signals initiate immunoglobulin light (Igl) chain gene assembly, leading to RAG-mediated DNA DSBs. The pre–BCR also promotes cell cycle entry, which could cause aberrant DSB repair and genome instability in pre–B cells. Here, we show that RAG DSBs inhibit pre–BCR signals through the ATM- and NF-κB2–dependent induction of SPIC, a hematopoietic-specific transcriptional repressor. SPIC inhibits expression of the SYK tyrosine kinase and BLNK adaptor, resulting in suppression of pre–BCR signaling. This regulatory circuit prevents the pre–BCR from inducing additional Igl chain gene rearrangements and driving pre–B cells with RAG DSBs into cycle. We propose that pre–B cells toggle between pre–BCR signals and a RAG DSB-dependent checkpoint to maintain genome stability while iteratively assembling Igl chain genes.

A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in Multiple Sclerosis

2019 ◽  
Vol 101 ◽  
pp. 1-16 ◽  
Author(s):  
Martina Severa ◽  
Fabiana Rizzo ◽  
Sundararajan Srinivasan ◽  
Marco Di Dario ◽  
Elena Giacomini ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cell ◽  
Type I Interferon ◽  
Type I ◽  
Cell Type ◽  
A Cell ◽  
Cell Type Specific

scholarly journals Modelling double strand break susceptibility to interrogate structural variation in cancer

2018 ◽  
Author(s):  
Tracy J. Ballinger ◽  
Britta Bouwman ◽  
Reza Mirzazadeh ◽  
Silvano Garnerone ◽  
Nicola Crosetto ◽  
...  
Keyword(s):  
Purifying Selection ◽  
Strand Break ◽  
Mutational Bias ◽  
Cell Type ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Rigorous Approach ◽  
Genome Wide ◽  
Functional Consequences ◽  
Cell Type Specific

AbstractBackgroundStructural variants (SVs) are known to play important roles in a variety of cancers, but their origins and functional consequences are still poorly understood. Many SVs are thought to emerge via errors in the repair processes following DNA double strand breaks (DSBs) and previous studies have experimentally measured DSB frequencies across the genome in cell lines.ResultsUsing these data we derive the first quantitative genome-wide models of DSB susceptibility, based upon underlying chromatin and sequence features. These models are accurate and provide novel insights into the mutational mechanisms generating DSBs. Models trained in one cell type can be successfully applied to others, but a substantial proportion of DSBs appear to reflect cell type specific processes. Using model predictions as a proxy for susceptibility to DSBs in tumours, many SV enriched regions appear to be poorly explained by selectively neutral mutational bias alone. A substantial number of these regions show unexpectedly high SV breakpoint frequencies given their predicted susceptibility to mutation, and are therefore credible targets of positive selection in tumours. These putatively positively selected SV hotspots are enriched for genes previously shown to be oncogenic. In contrast, several hundred regions across the genome show unexpectedly low levels of SVs, given their relatively high susceptibility to mutation. These novel ‘coldspot’ regions appear to be subject to purifying selection in tumours and are enriched for active promoters and enhancers.ConclusionsWe conclude that models of DSB susceptibility offer a rigorous approach to the inference of SVs putatively subject to selection in tumours.

ATM deficiency disrupts Tcra locus integrity and the maturation of CD4+CD8+ thymocytes

Blood ◽  
2006 ◽  
Vol 109 (5) ◽  
pp. 1887-1896 ◽  
Author(s):  
Irina R. Matei ◽  
Rebecca A. Gladdy ◽  
Lauryl M. J. Nutter ◽  
Angelo Canty ◽  
Cynthia J. Guidos ◽  
...  
Keyword(s):  
T Cell ◽  
Ataxia Telangiectasia ◽  
Cell Receptor ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Apoptotic Pathway ◽  
Strand Breaks ◽  
Striking Contrast

Abstract Mutations in ATM (ataxia-telangiectasia mutated) cause ataxia-telangiectasia (AT), a disease characterized by neurodegeneration, sterility, immunodeficiency, and T-cell leukemia. Defective ATM-mediated DNA damage responses underlie many aspects of the AT syndrome, but the basis for the immune deficiency has not been defined. ATM associates with DNA double-strand breaks (DSBs), and some evidence suggests that ATM may regulate V(D)J recombination. However, it remains unclear how ATM loss compromises lymphocyte development in vivo. Here, we show that T-cell receptor β (TCRβ)–dependent proliferation and production of TCRβlow CD4+CD8+ (DP) thymocytes occurred normally in Atm−/− mice. In striking contrast, the postmitotic maturation of TCRβlow DP precursors into TCRβint DP cells and TCRβhi mature thymocytes was profoundly impaired. Furthermore, Atm−/− thymocytes expressed abnormally low amounts of TCRα mRNA and protein. These defects were not attributable to the induction of a BCL-2–sensitive apoptotic pathway. Rather, they were associated with frequent biallelic loss of distal Va gene segments in DP thymocytes, revealing that ATM maintains Tcra locus integrity as it undergoes V(D)J recombination. Collectively, our data demonstrate that ATM loss increases the frequency of aberrant Tcra deletion events, which compromise DP thymocyte maturation and likely promote the generation of oncogenic TCR translocations.

scholarly journals IGH/MYC Translocation in Burkitt Lymphoma Is Associated with BRCA2 Deficiency and Synthetic Lethality By PARP1 Inhibitors

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4111-4111 ◽  
Author(s):  
Silvia Maifrede ◽  
Kayla Martin ◽  
Paulina Podszywalow-Bartnicka ◽  
Sullivan Katherine ◽  
Samantha Langer ◽  
...  
Keyword(s):  
B Cell ◽  
Burkitt Lymphoma ◽  
Research Funding ◽  
Synthetic Lethality ◽  
B Cell Lymphoma ◽  
Double Strand Breaks ◽  
University Of Pennsylvania ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Parp1 Inhibitors

Abstract Burkitt lymphoma/leukemia (BL) is a highly aggressive mature B-cell neoplasm characterized by chromosomal rearrangements of the c-myc oncogene resulting in the overexpression of MYC transcription factor. The most common translocation is the t(8;14)(q24;q32) (85% of all cases), which involves MYC and IGH loci to generate IGH/MYC. Deregulation of MYC, a potent proto-oncogene and transcriptional regulator contributes to lymphomagenesis through alterations in cell cycle regulation, and cell differentiation, apoptosis, adhesion, and metabolism. BL treatment consists of high-intensity chemotherapy protocols that include cyclophosphamide, cytarabine (AraC) and doxorubicin. Current therapies have achieved a very favorable outcome resulting in complete remission in 75% to 90% of BL patients and a survival rate of 70% to 80%. However the current treatment for BL is suboptimal in elderly patients or patients with advanced-stage diseased, in the setting of HIV infections, as well as in the setting of relapsed disease. Therefore new therapeutic strategies are necessary to improve the outcomes in BL diseases in the poor prognosis patients. It has been reported that overexpression of MYC caused accumulation of potentially lethal DNA double-strand breaks (DSBs), which can modulate the response of tumor cells to genotoxic treatment. Therefore, we examined the consequences of DSBs accumulation in IGH/MYC-positive BL cells. Here we show that untreated and cytarabine (AraC)-treated IGH/MYC-positive BL cells accumulate high number of potentially lethal DNA double-strand breaks (DSBs) and display downregulation of BRCA2 tumor suppressor protein, which is a key element of homologous recombination - mediated DSB repair. BRCA2 deficiency in IGH/MYC-positive cells was associated with hypersensitivity to PARP1 inhibitors (olaparib, talazoparib) used alone or in combination with cytarabine in vitro. Moreover, talazoparib exerted a therapeutic effect in NGS mice bearing primary BL xenografts. In conclusion, we postulate that BRCA2 deficiency may predispose BL cells to synthetic lethality triggered by PARP1 inhibitor, such as recently FDA approved olaparib. Moreover, PARP1 inhibitor may be useful for the treatment of other malignancies associated with deregulation of MYC, including diffuse large B-cell lymphoma (DLBCL) and ALK-positive LBCL. Disclosures Wasik: Gilead Sciences: Equity Ownership; Seattle Genetics: Honoraria; Novartis: Research Funding; University of Pennsylvania: Patents & Royalties: NPM-ALK as an omncogene; University of Pennsylvania: Patents & Royalties: CAR T-cells; Gilead Sciences: Research Funding; Pharmacyclics: Research Funding.

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