TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitors
Abstract Deletions of chromosome 1p (del(1p)) are a recurrent genomic aberration associated with poor outcome in Multiple myeloma (MM.) TRIM33, an E3 ligase and transcriptional co-repressor, is located within a commonly deleted region at 1p13.2. TRIM33 is reported to play a role in the regulation of...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-04-01
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| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-024-58828-8 |
| _version_ | 1797199456425213952 |
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| author | Roisin M. McAvera Jonathan J. Morgan Ana B. Herrero Ken I. Mills Lisa J. Crawford |
| author_facet | Roisin M. McAvera Jonathan J. Morgan Ana B. Herrero Ken I. Mills Lisa J. Crawford |
| author_sort | Roisin M. McAvera |
| collection | DOAJ |
| description | Abstract Deletions of chromosome 1p (del(1p)) are a recurrent genomic aberration associated with poor outcome in Multiple myeloma (MM.) TRIM33, an E3 ligase and transcriptional co-repressor, is located within a commonly deleted region at 1p13.2. TRIM33 is reported to play a role in the regulation of mitosis and PARP-dependent DNA damage response (DDR), both of which are important for maintenance of genome stability. Here, we demonstrate that MM patients with loss of TRIM33 exhibit increased chromosomal instability and poor outcome. Through knockdown studies, we show that TRIM33 loss induces a DDR defect, leading to accumulation of DNA double strand breaks (DSBs) and slower DNA repair kinetics, along with reduced efficiency of non-homologous end joining (NHEJ). Furthermore, TRIM33 loss results in dysregulated ubiquitination of ALC1, an important regulator of response to PARP inhibition. We show that TRIM33 knockdown sensitizes MM cells to the PARP inhibitor Olaparib, and this is synergistic with the standard of care therapy bortezomib, even in co-culture with bone marrow stromal cells (BMSCs). These findings suggest that TRIM33 loss contributes to the pathogenesis of high-risk MM and that this may be therapeutically exploited through the use of PARP inhibitors. |
| first_indexed | 2024-04-24T07:16:03Z |
| format | Article |
| id | doaj.art-43685fcf2e784080aa0b53d8bebdb850 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T07:16:03Z |
| publishDate | 2024-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-43685fcf2e784080aa0b53d8bebdb8502024-04-21T11:16:00ZengNature PortfolioScientific Reports2045-23222024-04-0114111110.1038/s41598-024-58828-8TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitorsRoisin M. McAvera0Jonathan J. Morgan1Ana B. Herrero2Ken I. Mills3Lisa J. Crawford4Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastPatrick G Johnston Centre for Cancer Research, Queen’s University BelfastInstitute of Biomedical Research of Salamanca (IBSAL)Patrick G Johnston Centre for Cancer Research, Queen’s University BelfastPatrick G Johnston Centre for Cancer Research, Queen’s University BelfastAbstract Deletions of chromosome 1p (del(1p)) are a recurrent genomic aberration associated with poor outcome in Multiple myeloma (MM.) TRIM33, an E3 ligase and transcriptional co-repressor, is located within a commonly deleted region at 1p13.2. TRIM33 is reported to play a role in the regulation of mitosis and PARP-dependent DNA damage response (DDR), both of which are important for maintenance of genome stability. Here, we demonstrate that MM patients with loss of TRIM33 exhibit increased chromosomal instability and poor outcome. Through knockdown studies, we show that TRIM33 loss induces a DDR defect, leading to accumulation of DNA double strand breaks (DSBs) and slower DNA repair kinetics, along with reduced efficiency of non-homologous end joining (NHEJ). Furthermore, TRIM33 loss results in dysregulated ubiquitination of ALC1, an important regulator of response to PARP inhibition. We show that TRIM33 knockdown sensitizes MM cells to the PARP inhibitor Olaparib, and this is synergistic with the standard of care therapy bortezomib, even in co-culture with bone marrow stromal cells (BMSCs). These findings suggest that TRIM33 loss contributes to the pathogenesis of high-risk MM and that this may be therapeutically exploited through the use of PARP inhibitors.https://doi.org/10.1038/s41598-024-58828-8Multiple myelomaDNA damage responseGenomic instabilityTRIM33PARP |
| spellingShingle | Roisin M. McAvera Jonathan J. Morgan Ana B. Herrero Ken I. Mills Lisa J. Crawford TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitors Scientific Reports Multiple myeloma DNA damage response Genomic instability TRIM33 PARP |
| title | TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitors |
| title_full | TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitors |
| title_fullStr | TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitors |
| title_full_unstemmed | TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitors |
| title_short | TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitors |
| title_sort | trim33 loss in multiple myeloma is associated with genomic instability and sensitivity to parp inhibitors |
| topic | Multiple myeloma DNA damage response Genomic instability TRIM33 PARP |
| url | https://doi.org/10.1038/s41598-024-58828-8 |
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