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该THO复合物抵消了TERRA R环介导的端粒脆弱性在端粒酶+细胞和端粒重组在ALT+细胞

Rita Valador Fernandes¹, Joachim Lingner¹

¹Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.

Nucleic acids research

|May 29, 2023

概括

在染色体末端,THO复合体 (THOC) 调节端粒重复含有RNA (TERRA) 的局部化. THOC可以防止TERRA R-循环,保持端粒稳定性,抑制癌细胞的重组.

科学领域:

遗传学是一个遗传学.
分子生物学分子生物学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

端粒保护染色体末端,并转录为包含重复的端粒RNA (TERRA).
已知THO复合体 (THOC) 将转录与RNA处理联系起来,并减少全基因组的DNA:RNA杂交物.
THOC在端粒中的特定作用及其对TERRA的调节在很大程度上仍未被探索.

研究的目的:

研究THO复合体 (THOC) 在调节人体端粒中端粒重复含有RNA (TERRA) 局部化的功能.
阐明THOC如何影响端粒中与TERRA相关的R环的形成和分离.
确定THOC对端粒稳定性,复制和重组的影响,特别是在癌细胞中.

主要方法:

染色体免疫沉以评估端粒中的THOC占用率.
在现场杂交 (FISH) 进行RNA光,以可视化TERRA本地化.
对端粒脆弱性和姐妹染色体交换的分析.
在替代延长端粒 (ALT) 癌细胞中评估C圆的形成.

主要成果:

通过解决R循环,THOC积极抵消TERRA与端粒的关联,无论是共转录还是后转录.
THOC结合于核等离子体TERRA,其对端粒的招募通过增加端粒R循环 (例如,在RNaseH1损失时) 得到增强.
THOC减轻端粒脆弱性,抑制端粒姐妹染色体交换和ALT癌细胞中C圆积累.

结论:

通过调节TERRA R-循环,THOC在维持端粒平衡中发挥着至关重要的作用.
THOC的功能扩展到防止复制叉问题和抑制癌症中的重组驱动的端粒维护.
准THOC可以为依赖端粒维持机制的癌症提供新的治疗策略.

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