Space and time in the universe of the cell nucleus after ionizing radiation attacks: a comparison of cancer and non-cancer cell response

M. Hausmann, Charlotte Neitzel, H. Hahn, Ruth Winter, I. Falková, D. Heermann, Goetz Pilarczyk, G. Hildenbrand, M. Falk
{"title":"Space and time in the universe of the cell nucleus after ionizing radiation attacks: a comparison of cancer and non-cancer cell response","authors":"M. Hausmann, Charlotte Neitzel, H. Hahn, Ruth Winter, I. Falková, D. Heermann, Goetz Pilarczyk, G. Hildenbrand, M. Falk","doi":"10.3390/iecc2021-09219","DOIUrl":null,"url":null,"abstract":"Application of ionizing radiation has an increasing impact on bio-medical research, and cancer diagnosis and treatment. Nevertheless, there are a lot of open questions concerning the understanding of radiation DNA damaging mechanisms and repair processes within the light of radio-sensitivity and thus, individualized medical applications. The three-dimensional architecture of genomes on the micro-, meso- and nano-scale acts in combination with epigenetic modifications as an important player of gene regulation and, consequently, fundamental biological processes such as DNA damage response and repair. So far only little is known about the impact of chromatin architecture on DNA double strand break (DSB) repair pathway selection and progression at individual damage sites. How does a cell nucleus manage DSBs and re-organize the chromatin towards functionally intact repair units? Is there a radiosensitivity-related difference in this reaction? We present investigations of spatial and topological parameters of chromatin and repair foci during a time period of repair to glimpse key aspects related to these questions. Nano-probing of radiation-induced chromatin damage sites and the recruited DNA repair proteins in combination with super-resolution Single Molecule Localization Microscopy (SMLM) are powerful methods for geometric and topological analyses of these structures in single cells and single DSB sites and, thus, to study mechanisms of their formation and repair pathway regulation. We used variable tools for such investigations based on image-free high-precision SMLM, nano-scaled molecule distribution analyses, appropriate metrics following Ripley´s distance frequencies and cluster formation analyses, as well as topological quantifications employing persistence homology. Comparing the topology of repair foci by persistence homology suggests general similarities in repair cluster formation, indicating a well-defined non-random, molecule topology at given time points during repair. However, at the same time, the data reveal a specific nano-architecture of DNA damage foci depending on the chromatin domain and cell type. Showing how chromatin architecture around complex damage sites and repair focus nano-architecture may contribute to ongoing repair process, our studies contribute to the molecular understanding of cellular radiation response and its regulation in cancer and non-cancer cells at sub-light microscopic chromatin levels.","PeriodicalId":20534,"journal":{"name":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2021-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Proceedings of The 1st International Electronic Conference on Cancers: Exploiting Cancer Vulnerability by Targeting the DNA Damage Response","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3390/iecc2021-09219","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 2

Abstract

Application of ionizing radiation has an increasing impact on bio-medical research, and cancer diagnosis and treatment. Nevertheless, there are a lot of open questions concerning the understanding of radiation DNA damaging mechanisms and repair processes within the light of radio-sensitivity and thus, individualized medical applications. The three-dimensional architecture of genomes on the micro-, meso- and nano-scale acts in combination with epigenetic modifications as an important player of gene regulation and, consequently, fundamental biological processes such as DNA damage response and repair. So far only little is known about the impact of chromatin architecture on DNA double strand break (DSB) repair pathway selection and progression at individual damage sites. How does a cell nucleus manage DSBs and re-organize the chromatin towards functionally intact repair units? Is there a radiosensitivity-related difference in this reaction? We present investigations of spatial and topological parameters of chromatin and repair foci during a time period of repair to glimpse key aspects related to these questions. Nano-probing of radiation-induced chromatin damage sites and the recruited DNA repair proteins in combination with super-resolution Single Molecule Localization Microscopy (SMLM) are powerful methods for geometric and topological analyses of these structures in single cells and single DSB sites and, thus, to study mechanisms of their formation and repair pathway regulation. We used variable tools for such investigations based on image-free high-precision SMLM, nano-scaled molecule distribution analyses, appropriate metrics following Ripley´s distance frequencies and cluster formation analyses, as well as topological quantifications employing persistence homology. Comparing the topology of repair foci by persistence homology suggests general similarities in repair cluster formation, indicating a well-defined non-random, molecule topology at given time points during repair. However, at the same time, the data reveal a specific nano-architecture of DNA damage foci depending on the chromatin domain and cell type. Showing how chromatin architecture around complex damage sites and repair focus nano-architecture may contribute to ongoing repair process, our studies contribute to the molecular understanding of cellular radiation response and its regulation in cancer and non-cancer cells at sub-light microscopic chromatin levels.
电离辐射攻击后细胞核在宇宙中的空间和时间:癌细胞和非癌细胞反应的比较
电离辐射的应用对生物医学研究、癌症诊断和治疗的影响越来越大。然而,从放射敏感性和个体化医疗应用的角度来看,对辐射DNA损伤机制和修复过程的理解仍有许多悬而未决的问题。基因组在微观、中观和纳米尺度上的三维结构与表观遗传修饰结合,在基因调控和DNA损伤反应和修复等基本生物过程中发挥着重要作用。到目前为止,人们对染色质结构对DNA双链断裂(DSB)修复途径选择和单个损伤位点进展的影响知之甚少。细胞核如何管理dsb并重新组织染色质以实现功能完整的修复单元?这种反应是否有放射敏感性相关的差异?我们提出了一段时间内染色质和修复焦点的空间和拓扑参数的调查,以瞥见与这些问题相关的关键方面。结合超分辨率单分子定位显微镜(SMLM)对辐射诱导的染色质损伤位点和募集的DNA修复蛋白进行纳米探测是对这些结构在单细胞和单个DSB位点进行几何和拓扑分析的有力方法,从而研究其形成和修复途径调控的机制。我们使用了各种工具来进行此类研究,这些工具基于无图像高精度SMLM、纳米尺度的分子分布分析、Ripley距离频率和聚类形成分析的适当度量,以及采用持久性同源性的拓扑量化。通过持续同源性比较修复焦点的拓扑结构表明,修复簇的形成具有普遍的相似性,表明在修复过程中的给定时间点具有明确的非随机分子拓扑结构。然而,与此同时,数据揭示了DNA损伤灶的特定纳米结构取决于染色质结构域和细胞类型。我们的研究显示了复杂损伤位点周围的染色质结构和修复焦点的纳米结构如何有助于正在进行的修复过程,我们的研究有助于在亚光微观染色质水平下对癌细胞和非癌细胞的细胞辐射反应及其调控的分子理解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信