E3 Ligase UBR5 HECT domain mutations in lymphoma control maturation of B cells via alternative splicing
| Autor: | Jared H. Graham, Shannon M. Buckley, R. Willow Hynes-Smith, Samantha A. Swenson, Henry Chun Hin Law, Nicholas T. Woods, Tyler J. Gilbreath, Heather Vahle, Michael R. Green |
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| Rok vydání: | 2019 |
| Předmět: |
HECT domain
0303 health sciences Spliceosome biology Alternative splicing Ubiquitin ligase Cell biology 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure Ubiquitin Immunoglobulin class switching 030220 oncology & carcinogenesis RNA splicing biology.protein medicine B cell 030304 developmental biology |
| DOI: | 10.1101/732180 |
| Popis: | Coordination of a number of molecular mechanisms including transcription, alternative splicing, and class switch recombination are required to facilitate development, activation, and survival of B cells. Disruption of these pathways can result in malignant transformation. Recently, next generation sequencing has identified a number of novel mutations in mantle cell lymphoma (MCL) patients including the ubiquitin E3 ligase UBR5. Approximately 18% of MCL patients were found to have mutations in UBR5 with the majority of mutations within the HECT domain of the protein which can accept and transfer ubiquitin molecules to the substrate. Determining if UBR5 controls the maturation of B cells is important to fully understand malignant transformation to MCL. To elucidate the role of UBR5 in B cell maturation and activation we generated a conditional mutant disrupting UBR5’s C-terminal HECT domain. Loss of the UBR5 HECT domain leads to a block in maturation of B cells in the spleen and up-regulation of proteins associated with mRNA splicing via the spliceosome. Our studies reveal a novel role of UBR5 in B cell maturation by regulating alternative splicing of key transcripts during B cell development and suggests UBR5 mutations may promote mantle cell lymphoma initiation.KEY POINTSUtilizing a novel mouse model mimicking MCL patient mutations, the loss of UBR5’s HECT domain causes alterations in B cell development.UBR5 mutations lead to stabilization of UBR5 and aberrant splicing. |
| Databáze: | OpenAIRE |
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