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4. 67. Long noncoding RNAs encoding peptides in cancer

Author

Coonrod, Emily, primary, Othoum, Ghofran, additional, Nickless, Andrew, additional, Zhang, Jin, additional, Inkman, Matthew, additional, Zhao, Sidi, additional, Dang, Ha, additional, Webster, Jace, additional, Rozycki, Emily, additional, Fontes, Sherron, additional, White, Nicole, additional, and Maher, Christopher, additional

Published
2022
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7. Intracellular calcium regulates nonsense-mediated mRNA decay

Author

Nickless, Andrew, Jackson, Erin, Marasa, Jayne, Nugent, Patrick, Mercer, Robert W., Piwnica-Worms, David, and You, Zhongsheng

Subjects
Adenosine triphosphatase -- Analysis, Messenger RNA -- Physiological aspects, Digoxin -- Physiological aspects, Ouabain -- Physiological aspects -- Health aspects, Biological sciences, Health, Washington University. School of Medicine
Abstract

The nonsense-mediated mRNA decay (NMD) pathway selectively eliminates aberrant transcripts containing premature translation termination codons and regulates the levels of a number of physiological mRNAs. NMD modulates the clinical outcome of a variety of human diseases, including cancer and many genetic disorders, and may represent a target for therapeutic intervention. Here, we have developed a new multicolored bioluminescence-based reporter system that can specifically and effectively assay NMD in live human cells. Using this reporter system, we conducted a robust high-throughput small-molecule screen in human cells and, unpredictably, identified a group of cardiac glycosides, including ouabain and digoxin, as potent inhibitors of NMD. Cardiac glycoside-mediated effects on NMD are dependent on binding and inhibiting the sodium-potassium ATPase on the plasma membrane and subsequent elevation of intracellular calcium levels. Induction of calcium release from the endoplasmic reticulum also leads to inhibition of NMD. Thus, this study reveals intracellular calcium as a key regulator of NMD and has implications for exploiting NMD in the treatment of disease., The NMD pathway selectively degrades mRNAs harboring premature translation termination codons (PTCs) and, in so doing, guards cells against insults from potentially deleterious truncated proteins. In addition to eliminating faulty [...]

Published
2014
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11. RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals

Author

Bednarski, Jeffrey J., primary, Pandey, Ruchi, additional, Schulte, Emily, additional, White, Lynn S., additional, Chen, Bo-Ruei, additional, Sandoval, Gabriel J., additional, Kohyama, Masako, additional, Haldar, Malay, additional, Nickless, Andrew, additional, Trott, Amanda, additional, Cheng, Genhong, additional, Murphy, Kenneth M., additional, Basing, Craig H., additional, Payton, Jacqueline E., additional, and Sleckman, Barry P., additional

Published
2016
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13. RAG-mediated DNA double-strand breaks activate a cell type–specific checkpoint to inhibit pre–B cell receptor signals

Author

Bednarski, Jeffrey J., Pandey, Ruchi, Schulte, Emily, White, Lynn S., Chen, Bo-Ruei, Sandoval, Gabriel J., Kohyama, Masako, Haldar, Malay, Nickless, Andrew, Trott, Amanda, Cheng, Genhong, Murphy, Kenneth M., Bassing, Craig H., Payton, Jacqueline E., and Sleckman, Barry P.

Abstract

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.

Published
2016
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14. RAG-induced DNA double-strand breaks signal through Pim2 to promote pre–B cell survival and limit proliferation

Author

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

Abstract

Interleukin 7 (IL-7) promotes pre–B cell survival and proliferation by activating the Pim1 and Akt kinases. These signals must be attenuated to induce G1 cell cycle arrest and expression of the RAG endonuclease, which are both required for IgL chain gene rearrangement. As lost IL-7 signals would limit pre–B cell survival, how cells survive during IgL chain gene rearrangement remains unclear. We show that RAG-induced DNA double-strand breaks (DSBs) generated during IgL chain gene assembly paradoxically promote pre–B cell survival. This occurs through the ATM-dependent induction of Pim2 kinase expression. Similar to Pim1, Pim2 phosphorylates BAD, which antagonizes the pro-apoptotic function of BAX. However, unlike IL-7 induction of Pim1, RAG DSB-mediated induction of Pim2 does not drive proliferation. Rather, Pim2 has antiproliferative functions that prevent the transit of pre–B cells harboring RAG DSBs from G1 into S phase, where these DNA breaks could be aberrantly repaired. Thus, signals from IL-7 and RAG DSBs activate distinct Pim kinase family members that have context-dependent activities in regulating pre–B cell proliferation and survival.

Published
2012
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15. Studying Nonsense-Mediated mRNA Decay in Mammalian Cells Using a Multicolored Bioluminescence-Based Reporter System.

Author

Nickless A and You Z

Subjects
Animals, Cell Line, Codon, Nonsense genetics, Cytomegalovirus genetics, Genes, T-Cell Receptor beta genetics, Humans, Luciferases chemistry, Luciferases genetics, Luminescence, Luminescent Measurements methods, RNA, Messenger isolation & purification, Genes, Reporter, Genetic Vectors genetics, Nonsense Mediated mRNA Decay, RNA, Messenger metabolism, Transfection methods
Abstract

The nonsense-mediated mRNA decay (NMD) pathway degrades aberrant transcripts containing premature translation termination codons (PTCs) and also regulates the levels of many normal mRNAs containing NMD-inducing features. The activity of this pathway varies considerably in different cell types and can change in response to developmental and environmental cues. Modulating NMD activity represents a potential therapeutic avenue for certain genetic disorders and cancers. Simple reporter systems capable of faithfully assessing NMD activity in mammalian cells greatly facilitate both basic and translational research on NMD. Here we describe a simple and effective method for assaying NMD specifically and quickly in live mammalian cells using a multicolored bioluminescence-based reporter system. This reporter can be transiently or stably introduced into cultured cells as well as animals, and NMD activity can be accurately assessed by bioluminescence imaging, western blot, or RT-qPCR.

Published
2018
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