The Chromosome Passenger Complex (CPC) Components and Its Associated Pathways Are Promising Candidates to Differentiate Between Normosensitive and Radiosensitive ATM-Mutated Cells.

IF 3.4 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Biomarker Insights Pub Date : 2024-10-30 eCollection Date: 2024-01-01 DOI:10.1177/11772719241274017
Anne Dietz, Prabal Subedi, Omid Azimzadeh, Lukas Duchrow, Felix Kaestle, Juliane Paetzold, Sarah Katharina Payer, Sabine Hornhardt, Christine von Toerne, Stefanie M Hauck, Bettina Kempkes, Cornelia Kuklik-Roos, Danielle Brandes, Arndt Borkhardt, Simone Moertl, Maria Gomolka
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Abstract

Background: Sensitivity to ionizing radiation differs between individuals, but there is a limited understanding of the biological mechanisms that account for these variations. One example of such mechanisms are the mutations in the ATM (mutated ataxia telangiectasia) gene, that cause the rare recessively inherited disease Ataxia telangiectasia (AT). Hallmark features include chromosomal instability and increased sensitivity to ionizing radiation (IR).

Objectives: To deepen the molecular understanding of radiosensitivity and to identify potential new markers to predict it, human ATM-mutated and proficient cells were compared on a proteomic level.

Design: In this study, we analyzed 3 cell lines from AT patients, with varying radiosensitivity, and 2 cell lines from healthy volunteers, 24 hours and 72 hours post-10 Gy irradiation.

Methods: We used label-free mass spectrometry to identify differences in signaling pathways after irradiation in normal and radiosensitive individuals. Cell viability was initially determined by water soluble tetrazolium (WST) assay and DNA damage response was analyzed with 53BP1 repair foci formation along with KRAB-associated protein 1 (KAP1) phosphorylation.

Results: Proteomic analysis identified 4028 proteins, which were used in subsequent in silico pathway enrichment analysis to predict affected biological pathways post-IR. In AT cells, networks were heterogeneous at both time points with no common pathway identified. Mitotic cell cycle progress was the most prominent pathway altered after IR in cells from healthy donors. In particular, components of the chromosome passenger complex (INCENP and CDCA8) were significantly downregulated after 72 hours. This could also be verified at the mRNA level.

Conclusion: Altogether, the most striking result was that proteins forming the chromosome passenger complex were downregulated after radiation exposure in healthy normosensitive control cells, but not in radiosensitive ATM-deficient cells. Thus, mitosis-associated proteins form an interesting compound to gain insights into the development and prediction of radiosensitivity.

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染色体乘客复合体(CPC)成分及其相关途径有望区分正常敏感细胞和辐射敏感的ATM突变细胞。
背景:对电离辐射的敏感性因人而异,但人们对造成这些差异的生物机制了解有限。其中一个例子就是ATM(突变共济失调毛细血管扩张症)基因的突变,这种突变导致了罕见的隐性遗传疾病共济失调毛细血管扩张症(AT)。其特征包括染色体不稳定和对电离辐射(IR)的敏感性增加:为了加深对辐射敏感性的分子认识并确定预测辐射敏感性的潜在新标记,我们在蛋白质组水平上对人类ATM突变细胞和熟练细胞进行了比较:在这项研究中,我们分析了来自AT患者的3个细胞系(它们具有不同的辐射敏感性)和来自健康志愿者的2个细胞系(在10 Gy照射后24小时和72小时):方法:我们使用无标记质谱法来确定正常人和辐射敏感者接受辐照后信号通路的差异。通过水溶性四氮唑(WST)测定法初步确定细胞活力,并通过 53BP1 修复灶的形成和 KRAB 相关蛋白 1 (KAP1) 磷酸化分析 DNA 损伤反应:蛋白质组分析确定了 4028 个蛋白质,这些蛋白质被用于随后的硅通路富集分析,以预测感染 IR 后受影响的生物通路。在 AT 细胞中,两个时间点的网络都是异质的,没有发现共同的通路。在健康供体的细胞中,有丝分裂细胞周期进展是红外照射后发生改变的最主要途径。特别是,染色体客体复合物(INCENP 和 CDCA8)的成分在 72 小时后显著下调。这也可以在 mRNA 水平上得到验证:总之,最引人注目的结果是,在健康的正常敏感对照细胞中,形成染色体乘客复合体的蛋白质在辐照后下调,而在辐射敏感的ATM缺陷细胞中则没有。因此,有丝分裂相关蛋白是一种有趣的化合物,有助于深入了解辐射敏感性的发展和预测。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Biomarker Insights
Biomarker Insights MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.00
自引率
0.00%
发文量
26
审稿时长
8 weeks
期刊介绍: An open access, peer reviewed electronic journal that covers all aspects of biomarker research and clinical applications.
期刊最新文献
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