Abstract 5614: Mechanical regulation of cisplatin-DNA adduct repair in mesenchymal stem cells

Abstract

Abstract This study examined whether loss of mechanotransduction in pluripotent mesenchymal stem cells (MSCs) disrupted repair of bulky DNA adducts, such as those induced by ultraviolet light or cisplatin. MSCs are important for the maintenance and responsiveness of skeletal tissues to environmental mechanical challenges. Beyond regulating proliferative and differentiative capacity of MSCs, emerging evidence suggests that physical activity is associated with improved recovery from DNA damage caused by environmental genotoxic stressors associated with stress and aging. Highlighting the possible crosstalk between DNA repair and bone health, defects in nucleotide excision repair (NER), which removes bulky DNA adducts, are associated with myelosuppression and progeroid aging phenotypes that result in bone defects and lipidodystrophies in mice. Cancer, early aging syndromes, and certain musculoskeletal diseases are associated with disruption of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex that transduces environmental mechanical signals from the extracellular matrix into the nucleus of a cell. Loss of LINC complex elements is associated with breast cancer progression and poorer prognosis. We hypothesize that LINC-mediated mechanical stimulation into the nucleus is critical for repair of bulky DNA adducts. Our pilot project showed that mechanical stimulation applied in the form of low intensity vibration (LIV) improved NER of cisplatin-induced DNA adducts in cultured MSCs. Our findings show a 20% increase in repair of cisplatin-induced DNA adducts in LIV treated samples compared to non-vibrated samples at 24 hours (P<0.005). We also quantified the effect of LINC complex disruption on cisplatin-induced DNA damage removal. Intact MSCs showed significant adduct removal after 24 hours, while LINC disruption significantly reduced DNA repair (P<0.001). Furthermore, initial experiments suggest that LINC disrupted cells do not arrest at DNA repair checkpoints, therefore, loss of LINC complex may reduce entry into senescence increasing DNA mutagenesis. In conclusion, these findings suggest a novel interaction between mechanical stimulation, the DNA damage response, and LINC complex in DNA repair in multipotent mesenchymal stem cells. Furthermore, we suggest that LINC-mediated mechanical changes associated with LIV treatment may lead to novel therapeutic approaches to combat deleterious musculoskeletal conditions associated with anti-cancer treatments. Citation Format: Anamaria Gabriella Zavala, Nina Nikitina, Crystal Cantu, Dalia DeLaCruz, Gunes Uzer. Mechanical regulation of cisplatin-DNA adduct repair in mesenchymal stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5614.