Micronuclei-based model system reveals functional consequences of chromothripsis in human cells
Micronuclei-based model system reveals functional consequences of chromothripsis in human cells
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DOI：
10.7554/elife.50292
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发表时间：
2019-11-28
期刊：
影响因子：
7.7
通讯作者：
Storchova, Zuzana
中科院分区：
文献类型：
--
作者：
Kneissig, Maja;Keuper, Kristina;Storchova, Zuzana
癌细胞通常含有数量异常和结构异常的染色体。这些染色体畸变的后果很难在癌症中研究，因此近年来已经开发了几种模型系统。我们发现，通过微细胞介导的染色体转移工程化的额外染色体的人类细胞经常获得大量的染色体重排。重排是由染色体破碎和重新连接以及复制依赖机制引起的。我们发现，分离的微核缺乏功能核纤层蛋白B1，变得容易包膜破裂，导致DNA损伤和异常复制。功能核纤层蛋白B1的存在与微核大小部分相关，这表明核被膜的正确组装可能对膜曲率敏感。与没有重排的细胞相比，三体细胞中的染色体重排提供了生长优势。我们的模型系统能够研究任何染色体的大规模染色体重排机制及其在人类细胞中的后果。
Cancer cells often harbor chromosomes in abnormal numbers and with aberrant structure. The consequences of these chromosomal aberrations are difficult to study in cancer, and therefore several model systems have been developed in recent years. We show that human cells with extra chromosome engineered via microcell-mediated chromosome transfer often gain massive chromosomal rearrangements. The rearrangements arose by chromosome shattering and rejoining as well as by replication-dependent mechanisms. We show that the isolated micronuclei lack functional lamin B1 and become prone to envelope rupture, which leads to DNA damage and aberrant replication. The presence of functional lamin B1 partly correlates with micronuclei size, suggesting that the proper assembly of nuclear envelope might be sensitive to membrane curvature. The chromosomal rearrangements in trisomic cells provide growth advantage compared to cells without rearrangements. Our model system enables to study mechanisms of massive chromosomal rearrangements of any chromosome and their consequences in human cells.