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由端粒危机引发的染色体和 Kataegis

John Maciejowski¹, Yilong Li², Nazario Bosco¹

¹Laboratory for Cell Biology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.

|December 22, 2015

概括

端粒危机导致二心染色体形成染色体桥梁,导致基因组不稳定. 酶TREX1有助于解决这些桥梁,可能导致与癌症相关的DNA碎片化,如染色体.

科学领域:

遗传学
癌症生物学
分子生物学

背景情况:

端粒危机是一种广泛的端粒融合状态,与癌症的发展有关.
在端粒危机期间形成的二中性染色体被假定会导致基因组不稳定.
了解二心染色体的命运对于癌症研究至关重要.

研究的目的:

在端粒危机期间调查二心的人类染色体的行为和后果.
阐明核酶TREX1在染色体桥梁的分辨率中的作用.
探索端粒危机,二心染色体和癌症中随后的基因组变化之间的联系.

主要方法:

在端粒危机模型中通过线粒分裂观察二心染色体动态.
对染色体桥梁形成,核膜破裂和DNA单链形成的分析.
用CRISPR-Cas9基因编辑来评估TREX1在桥梁分辨率中的功能.
在危机后的癌症克隆中检查基因组变异 (染色体变, kataegis).

主要成果:

双中心染色体始终形成长长的染色体桥梁,连接子细胞.
这些桥梁诱导核膜破裂,招募TREX1,并积累了RPA涂层的单链DNA.
发现TREX1对于ssDNA生成和染色体桥梁分离至关重要.
危机后的细胞表现出染色体和 kataegis, 这表明DNA修复和编辑碎片桥梁.

结论:

双中心染色体在端粒危机中作为染色体桥梁存在,导致基因组不稳定.
在这些染色体桥梁的分离中,TREX1起着重要作用.
双中心染色体的TREX1媒介碎片化是人类癌症染色体变的潜在机制.

关键词:

在APOBEC 在 NERDI 在TREX1中染色体两个中心的染色体卡塔吉斯端粒危机

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