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Methylglyoxal induces chromosomal instability and mitotic dysfunction in lymphocytes
Mutagenesis ( IF 2.5 ) Pub Date : 2021-07-23 , DOI: 10.1093/mutage/geab028
Leigh Donnellan 1 , Bradley Simpson 1 , Varinderpal S Dhillon 1 , Maurizio Costabile 1, 2 , Michael Fenech 1, 3, 4 , Permal Deo 1
Affiliation  

Type 2 diabetes is associated with elevated levels of DNA damage, in particular micronuclei (MNi) which are formed by acentric chromosome fragments caused by double-stranded DNA breaks (DSBs), or whole chromosomes which fail to segregate during mitosis. We investigated if methylglyoxal (MGO), a reactive dicarbonyl known to be elevated in type 2 diabetes is capable of increasing chromosomal instability and DNA damage as measured by the cytokinesis block micronucleus cytome (CBMNcyt) assay in B-lymphoblastoid WIL2-NS cells and primary peripheral blood lymphocytes (PBL). We also investigated the level of various dicarbonyl stress biomarkers, including extracellular and intracellular MGO, protein and MGO modifications of DNA. WIL2-NS cells exposed to either MGO or a glyoxalase 1 inhibitor showed increases in MNi and nuclear buds, which were associated with an increase in intracellular MGO. DNA damage in the form of MNi and nucleoplasmic bridges were observed in primary PBL exposed to 10 µM MGO, suggesting low concentrations of MGO may be genotoxic. Furthermore, we showed, using fluorescent in situ hybridisation, that the majority of MNi caused by MGO in WIL2-NS cells were caused by whole chromosome loss events, rather than DSBs. Our data suggest that MGO, a reactive metabolite elevated in type 2 diabetes and other pathologies, can affect genomic integrity by impairing chromosome segregation during mitosis.

中文翻译:

甲基乙二醛诱导淋巴细胞染色体不稳定和有丝分裂功能障碍

2 型糖尿病与 DNA 损伤水平升高有关,特别是由双链 DNA 断裂 (DSB) 引起的无着丝粒染色体片段或在有丝分裂期间未能分离的整个染色体形成的微核 (MNi)。我们研究了甲基乙二醛 (MGO),一种已知在 2 型糖尿病中升高的反应性二羰基化合物是否能够增加染色体不稳定性和 DNA 损伤,如通过 B 淋巴母细胞样 WIL2-NS 细胞和原代细胞中的胞质分裂阻断微核细胞组 (CBMNcyt) 测定所测量的外周血淋巴细胞(PBL)。我们还研究了各种二羰基应激生物标志物的水平,包括细胞外和细胞内 MGO、蛋白质和 DNA 的 MGO 修饰。暴露于 MGO 或乙二醛酶 1 抑制剂的 WIL2-NS 细胞显示 MNi 和核芽增加,这与细胞内 MGO 的增加有关。在暴露于 10 µM MGO 的初级 PBL 中观察到 MNi 和核质桥形式的 DNA 损伤,这表明低浓度的 MGO 可能具有遗传毒性。此外,我们使用荧光原位杂交表明,WIL2-NS 细胞中由 MGO 引起的大多数 MNi 是由整个染色体丢失事件引起的,而不是由 DSB 引起的。我们的数据表明,MGO 是一种在 2 型糖尿病和其他疾病中升高的反应性代谢物,可通过在有丝分裂期间损害染色体分离来影响基因组完整性。在 WIL2-NS 细胞中由 MGO 引起的大多数 MNi 是由整个染色体丢失事件引起的,而不是由 DSBs 引起的。我们的数据表明,MGO 是一种在 2 型糖尿病和其他疾病中升高的反应性代谢物,可通过在有丝分裂期间损害染色体分离来影响基因组完整性。在 WIL2-NS 细胞中由 MGO 引起的大多数 MNi 是由整个染色体丢失事件引起的,而不是由 DSBs 引起的。我们的数据表明,MGO 是一种在 2 型糖尿病和其他疾病中升高的反应性代谢物,可通过在有丝分裂期间损害染色体分离来影响基因组完整性。
更新日期:2021-07-23
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