ATR限制了Rad18介导的PCNA单双化,以保持复制叉和与端粒酶无关的端粒稳定性
Siyuan Chen1,2, Chen Pan2, Jun Huang3,4,5
1Zhejiang Provincial Key Laboratory of Geriatrics and Geriatrics Institute of Zhejiang Province, Affiliated Zhejiang Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China.
The EMBO journal
|March 12, 2024
概括
ATAXIA telangiectasia-mutated和Rad3相关的 (ATR) 激酶通过酸化Rad18来阻止复制叉的崩,这限制了PCNA单双化和过度的SLX4积累. 这种机制保护ALT细胞中的端粒稳定性.
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 遗传学 是一个
背景情况:
- 复制分叉的停滞触发了ATAXIA telangiectasia-mutated和Rad3相关的 (ATR) 激酶激活和Rad18依赖的PCNA单双化.
- 在ATR激活和PCNA单双化之间的交叉声和其生理学意义尚未得到充分理解.
研究的目的:
- 为了研究在复制应激过程中ATR,Rad18和PCNA单双化之间的相互作用.
- 阐明这种相互作用在防止停滞分叉崩和保持端粒稳定性方面的作用.
主要方法:
- 人类Rad18.8的酸化部位映射.
- 使用共免疫沉对蛋白质-蛋白质相互作用的分析.
- 评估PCNA单双化水平.
- 对SLX4.4的细胞局部化研究.
- 端粒稳定性测试用于替代延长端粒 (ALT) 细胞.
主要成果:
- ATR在Ser403上对人类Rad18进行酸化,与一种新的PIP动机相邻.
- 这种酸化破坏了Rad18-PCNA相互作用,限制了PCNA单双化.
- 防止SLX4在停滞的叉子上过度积累.
- 在ALT细胞中,ATR通过限制Rad18介导的PCNA单双化和SLX4积累来保持端粒稳定性.
结论:
- 通过ATR介导的Rad18酸化是一种关键的调节机制,可以控制复制应激期间的PCNA单双化.
- 这一途径防止停滞叉崩,并保持ALT细胞中的端粒稳定性.
- 这些发现揭示了SLX4作为无处不在的PCNA读者的新角色,并突出了ATR在基因组稳定性的重要性.
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