在复制应激下,ATR通过CENP-A从中间体中驱逐促进基因组不稳定
Denis Ostapenko1,2, Hang Li1,2, Isabelle Trier1,2
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511.
bioRxiv : the preprint server for biology
|November 24, 2025
概括
复制应激会导致中心体中CENP-A的损失,导致基因组不稳定. 这一过程由ATR激酶介导,导致非中心的染色体和细胞周期缺陷.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 遗传学 是一个遗传学.
背景情况:
- 复制压力是已知的基因组不稳定的驱动因素.
- 连接复制应激与中粒体功能障碍和染色体错误分离的确切机制尚不清楚.
研究的目的:
- 阐明复制应激影响中粒体功能的分子机制.
- 在复制压力下识别涉及中粒体功能障碍的关键蛋白质和途径.
主要方法:
- 利用了人类和小鼠细胞模型.
- 研究了ATR激酶和VCP在应对复制压力的作用.
- 使用生化和成像技术检查了CENP-A定位和核细胞稳定性.
主要成果:
- 持续的复制应激会诱导从中间体中驱逐素H3变异CENP-A.
- 通过招募VCP,ATR激酶促进CENP-A驱逐,从而破坏CENP-A核细胞的稳定.
- 被驱逐的CENP-A定位到核细胞,依赖于HJURP.
- 在细胞周期重新进入后,依赖ATR的CENP-A驱逐仍然存在,与非中心染色体形成相关.
结论:
- 复制压力通过ATR-依赖的CENP-A驱逐直接损害了中间体的身份.
- 这一途径将复制压力与染色体错误分离和基因组不稳定性联系起来.
- 确定了ATR在压力下调节中心分子稳定性的新型作用.
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