Loss of TRIM33 Leads to Chromosomal Instability and Increased Endogenous DNA Damage in Multiple Myeloma

Multiple Myeloma (MM) is an incurable haematological malignancy characterised by the clonal proliferation of plasma cells. Deletion of chromosome 1p (del1p) is a common genetic event associated with high-risk MM. Located within this region at 1p13.2 is TRIM33, a chromatin-associated E3 ligase which can function as a transcriptional co-repressor. Recent studies have shown that TRIM33 functions in the PARP-dependent DNA Damage Response (DDR). However, its molecular function during the DDR remains unclear. Here, we investigated the impact of TRIM33 loss on genome stability and the DDR in MM. Using the publicly available CoMMpass (Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile) dataset, we identified 69 (9.5%) out of 730 newly diagnosed MM patients that had a copy number loss of TRIM33. Kaplan-Meier analysis revealed that these patients have a poorer overall survival compared to those without TRIM33 loss (median 52.3 months vs 72.6 months; p<0.0001). In addition, these patients have a significantly higher number of structural variants (median 38 vs 26; p<0.0001) indicative of increased chromosomal instability. We show that TRIM33 is rapidly recruited to chromatin following 2Gy irradiation, where it transiently interacts with the chromatin remodelling enzyme ALC1. Western blotting and immunofluorescence staining revealed an increase in double-strand break markers γH2AX and 53BP1 (p<0.001) in TRIM33 knockdown cells, along with increased expression of key HR protein RAD51 (p<0.01). MM patients with loss of TRIM33 similarly exhibited significantly higher gene expression of 53BP1 and RAD51 (p<0.0001) indicating a potential HR dysregulation. We have demonstrated that TRIM33 loss results in chromosomal instability and increased endogenous DNA damage in MM, typical of a DDR defect. Further understanding the role of TRIM33 in the DDR may lead to opportunities to therapeutically exploit DDR defects in patients with TRIM33 loss.