AI Article Synopsis
- A specific mutation in the IRF4 gene, associated with classic Hodgkin lymphoma, alters the protein's ability to bind to DNA, changing its normal functions.
- This mutation leads to a loss of typical interactions with certain DNA motifs while allowing new, atypical DNA binding interactions.
- The findings reveal how one mutation can significantly change the behavior of a transcription factor, potentially offering targeted treatment strategies that inhibit its abnormal activity.
Article Abstract
Disease-causing mutations in genes encoding transcription factors (TFs) can affect TF interactions with their cognate DNA-binding motifs. Whether and how TF mutations impact upon the binding to TF composite elements (CE) and the interaction with other TFs is unclear. Here, we report a distinct mechanism of TF alteration in human lymphomas with perturbed B cell identity, in particular classic Hodgkin lymphoma. It is caused by a recurrent somatic missense mutation c.295 T > C (p.Cys99Arg; p.C99R) targeting the center of the DNA-binding domain of Interferon Regulatory Factor 4 (IRF4), a key TF in immune cells. IRF4-C99R fundamentally alters IRF4 DNA-binding, with loss-of-binding to canonical IRF motifs and neomorphic gain-of-binding to canonical and non-canonical IRF CEs. IRF4-C99R thoroughly modifies IRF4 function by blocking IRF4-dependent plasma cell induction, and up-regulates disease-specific genes in a non-canonical Activator Protein-1 (AP-1)-IRF-CE (AICE)-dependent manner. Our data explain how a single mutation causes a complex switch of TF specificity and gene regulation and open the perspective to specifically block the neomorphic DNA-binding activities of a mutant TF.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10630337 | PMC |
| http://dx.doi.org/10.1038/s41467-023-41954-8 | DOI Listing |
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