Journal article
ATM-dependent Phosphorylation of Nemo SQ Motifs Is Dispensable for Nemo-mediated Gene Expression Changes in Response to DNA Double-Strand Breaks
The Journal of immunology (1950), v 213(5), pp 628-640
01 Sep 2024
PMID: 39007641
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
In response to DNA double-strand breaks (DSBs), the ATM kinase activates NF-κB factors to stimulate gene expression changes that promote survival and allow time for cells to repair damage. In cell lines, ATM can activate NF-κB transcription factors via two independent, convergent mechanisms. One is ATM-mediated phosphorylation of nuclear NF-κB essential modulator (Nemo) protein, which leads to monoubiquitylation and export of Nemo to the cytoplasm where it engages the IκB kinase (IKK) complex to activate NF-κB. Another is DSB-triggered migration of ATM into the cytoplasm, where it promotes monoubiquitylation of Nemo and the resulting IKK-mediated activation of NF-κB. ATM has many other functions in the DSB response beyond activation of NF-κB, and Nemo activates NF-κB downstream of diverse stimuli, including developmental or proinflammatory stimuli such as LPSs. To elucidate the in vivo role of DSB-induced, ATM-dependent changes in expression of NF-κB-responsive genes, we generated mice expressing phosphomutant Nemo protein lacking consensus SQ sites for phosphorylation by ATM or related kinases. We demonstrate that these mice are viable/healthy and fertile and exhibit overall normal B and T lymphocyte development. Moreover, treatment of their B lineage cells with LPS induces normal NF-κB-regulated gene expression changes. Furthermore, in marked contrast to results from a pre-B cell line, primary B lineage cells expressing phosphomutant Nemo treated with the genotoxic drug etoposide induce normal ATM- and Nemo-dependent changes in expression of NF-κB-regulated genes. Our data demonstrate that ATM-dependent phosphorylation of Nemo SQ motifs in vivo is dispensable for DSB-signaled changes in expression of NF-κB-regulated genes.
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Details
- Title
- ATM-dependent Phosphorylation of Nemo SQ Motifs Is Dispensable for Nemo-mediated Gene Expression Changes in Response to DNA Double-Strand Breaks
- Creators
- Rebecca A Glynn - University of PennsylvaniaKatharina E Hayer - Drexel UniversityCraig H Bassing (Corresponding Author) - Children's Hospital of Philadelphia
- Publication Details
- The Journal of immunology (1950), v 213(5), pp 628-640
- Publisher
- Oxford University Press
- Grant note
- T32 GM-07229 / HHS | NIH | National Institute of General Medical Sciences (NIGMS) R01 AI143661 / NIAID NIH HHS F31 AI152354 / NIAID NIH HHS R01 AI112621 / NIAID NIH HHS R01 AI 130231 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) R01 AI130231 / NIAID NIH HHS T32 GM007229 / NIGMS NIH HHS F31 AI 152354 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) R01 AI172163 / NIAID NIH HHS R01 AI 112621 / HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering and Science
- Web of Science ID
- WOS:001338100000011
- Scopus ID
- 2-s2.0-85201768975
- Other Identifier
- 991022202494404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology