Summary Chronic infection with Plasmodium falciparum was epidemiologically associated with endemic Burkitt’s lymphoma, a mature B cell cancer characterized by chromosome translocation between the c-myc oncogene and Igh, over 50 years ago. Whether infection promotes B cell lymphoma, and if so by what mechanism remains unknown. To investigate the relationship between parasitic disease and lymphomagenesis we used Plasmodium chabaudi (Pc) to produce chronic malaria infection in mice. Pc induces prolonged expansion of germinal centers (GCs), unique compartments where B cells undergo rapid clonal expansion and express activation-induced cytidine deaminase (AID), a DNA mutator. GC B cells elicited during Pc infection suffer widespread DNA damage leading to chromosome translocations. Although infection does not change the overall rate, it modifies lymphomagenesis to favor mature B cell lymphomas that are AID dependent and show chromosome translocations. Thus, malaria infection favors mature B cell cancers by eliciting protracted AID expression in GC B cells.
Background: Association of the proteasome core with activators regulates proteasome activity. Results: Blm10 association increases proteasome activity toward peptides and the unstructured proteasome substrate tau-441. This process is mediated by the C terminus of Blm10. Conclusion: C-terminal docking-mediated proteasome activation by Blm10 facilitates the turnover of peptide and protein substrates. Significance: Blm10 contributes to the regulation of proteasome activity.
AID promotes chromosomal translocations by inducing DNA double-strand breaks (DSBs) at immunoglobulin (Ig) genes and oncogenes in G1. RPA is a ssDNA-binding protein that associates with resected DSBs in the S phase and facilitates the assembly of factors involved in homologous repair (HR) such as Rad51. Notably, RPA deposition also marks sites of AID-mediated damage, but its role in Ig gene recombination remains unclear. Here we demonstrate that RPA associates asymmetrically with resected ssDNA in response to lesions created by AID, RAG, or other nucleases. Small amounts of RPA are deposited at AID targets in G1 in an ATM-dependent manner. In contrast, recruitment in S-G2/M is extensive, ATM-independent, and associated with Rad51 accumulation. RPA in S-G2/M increases in NHEJ-deficient lymphocytes, where there is more extensive DNA-end resection. Thus, most RPA recruitment during CSR represents salvage of un-repaired breaks by homology-based pathways during the S-G2/M phases of the cell cycle.
CtBP-interacting protein, exonuclease 1, and RecQ helicases contribute to the processing of DNA ends during double-strand break repairs in primary lymphocytes.
Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γc) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γc cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD–IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.
The Aicda gene encodes Activation-Induced cytidine Deaminase (AID), an enzyme essential for remodeling antibody genes in mature B lymphocytes. AID is also responsible for DNA damage at oncogenes, leading to their mutation and cancer-associated chromosome translocation in lymphoma. We used fate mapping and AIDGFP reporter mice to determine if AID expression in the mouse extends beyond lymphocytes. We discovered that AIDcre tags a small fraction of non-lymphoid cells starting at 10.5 days post conception (dpc), and that AIDGFP+ cells are detectable at dpc 11.5 and 12.5. Embryonic cells are tagged by AIDcre in the submandibular region, where conditional deletion of the tumor suppressor PTEN causes squamous papillomas. AIDcre also tags non-lymphoid cells in the embryonic central nervous system. Finally, in the adult mouse brain, AIDcre marks a small fraction of diverse neurons and distinct neuronal populations, including pyramidal cells in cortical layer IV.
The proteasome, a multicatalytic protease, displays distinct chymotrypsin-like, caspase-like, and trypsin-like activities at three different subunits of the multimeric complex. Fluorescent substrates for each of these active sites have been described. However, since the fluorescent properties of these substrates are very similar, it is not possible to simultaneously monitor catalysis of two or more activities. We have developed a long wavelength (λ ex = 600 nm, λ em = 700 nm) fluorescent substrate for the chymotrypsin-like active site via a combinatorial library strategy. This peptide-based substrate is a highly selective proteasomal chymotrypsin-like sensor, as assessed by a series of proteasomal active site mutants in yeast cell lysates. A corresponding caged analog of the sensor has been prepared, which is resistant to proteolysis until activated by 349 nm light. The latter affords the opportunity to assess proteasomal activity with a high degree of temporal control. The distinct photophysical properties of the sensor allow the chymotrypsin-like activity to be simultaneously monitored during caspase-like or trypsin-like catalysis. We have found that chymotrypsin-like activity is enhanced in the presence of the trypsin-like substrate, but reduced in the presence of caspase-like substrate. Furthermore, the chymotrypsin-like sensor hinders the activity of both the caspase-and trypsin-like active sites. Coincident monitoring of two catalytic active sites furnishes two-thirds coverage of total proteasomal activity, which should provide the means to address if and how the distinct active sites of the proteasome influence one another during catalysis.Aberrant pathways responsible for cancerous cell growth are remarkably plastic, endowing transformed cells with an extraordinary resilience against inhibitory (anticancer) agents. As a consequence, there is emerging evidence that the future of cancer chemotherapy lies in targeting multiple members of abnormal biochemical networks.1 In an analogous vein, the ability to simultaneously measure the catalytic activity at several sites in a network offers the means to detect aberrant biochemical behavior, screen for new inhibitory agents on a more global biochemical scale, and potentially predict the efficacy of various chemotherapeutic cocktails for individual patients. Conspiring biochemical activity may reside at distinct intracellular sites, within the same organelle, or as part of a single protein complex. An especially beautiful, yet challenging, example of the latter is the proteasome, which serves as the primary protein digestive apparatus in the cytoplasm and nuclei of eukaryotic cells.2 mschmidt@aecom.yu.edu and lawrencd@email.unc.edu. Supporting Information. Details of the yeast strains, the thirty-two-member peptide library, fluorescent and enzymological analysis of sensor 5, and photoconversion of caged 10 to its uncaged counterpart. This information is available free of charge via the Internet at
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