USP37通过抵消CUL2LRR1和TRAIP,在DNA复制压力期间保护哺乳动物细胞
Fabrizio Villa1, Johanna Ainsworth1, Karim P M Labib1
1Division of Genome Integrity, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Cell reports
|May 24, 2025
概括
USP37 deubiquitylase通过调节CMG螺旋酶来保护细胞免受DNA复制压力. 它通过抵消CUL2LRR1和TRAIP结合酶活性来防止过早的复杂细胞分解.
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:
- DNA复制压力对哺乳动物细胞生存构成重大威胁.
- 细胞管理复制压力的精确机制,特别是涉及复制体,仍然不完全理解.
研究的目的:
- 阐明USP37二维基酶在DNA复制压力期间哺乳动物细胞存活中的作用.
- 确定USP37调解其保护功能的分子标和机制.
主要方法:
- 同免疫沉测试以确定USP37交互的合作伙伴.
- 结构引导的突变发生来探测USP37-CMG相互作用.
- 对DNA复制抑制剂和拓压力的细胞敏感性测定.
- 乌比基连酶CUL2LRR1和TRAIP的耗尽和突变研究.
主要成果:
- 在复制分叉中,USP37直接与CMG酶的CDC45成分结合.
- USP37对抗由CUL2介导的CMG酶的无处不在和分解.
- 失去USP37功能会对DNA合成缺陷和ATR抑制剂产生敏感性,这种敏感性是由CUL2LRR1耗尽抑制的.
- 特别影响USP37突变者对拓应激的敏感性.
结论:
- USP37是一种关键的双双基酶,通过防止在复制压力期间过早的复制体分解来保护基因组.
- USP37的功能是通过逆转CMG螺旋酶上的CUL2LRR1和TRAIP无处不在酶的无处不在活性来发挥作用.
- 准USP37或其相互作用的链酶可能为管理复制压力相关条件提供治疗策略.
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