双重二维基因酶USP28集成了53BP1和MYC的功能,以限制DNA损伤
Chao Jin1,2, Elias Einig1,2, Wenshan Xu3
1Department of Medical Oncology and Pulmonology, University Hospital Tübingen, Otfried-Müller-Str 14, 72076 Tübingen, Germany.
Nucleic acids research
|January 16, 2024
概括
USP28蛋白质二元化可以防止异常的DNA复制和损伤. 压力破坏了这种二分化,增加了复制和DNA损伤,揭示了基因组稳定性的关键机制.
科学领域:
- 分子生物学分子生物学
- 癌症生物学 癌症生物学
- 遗传学 遗传学 是一个
背景情况:
- DNA复制是癌细胞中DNA损伤的主要来源.
- 在癌症中普遍存在的基蛋白MYC可以放松DNA复制的调节.
- 针对MYC的二维基因酶USP28也通过53BP1.1调解DNA损伤反应.
研究的目的:
- 为了研究USP28二元化的生物学作用.
- 了解USP28二元化如何影响MYC活动和DNA复制.
- 阐明USP28,53BP1和DNA损伤反应之间的相互作用.
主要方法:
- 通过生物化学和细胞分析研究了USP28二元化.
- 评估了USP28单体与二体形式对MYC招募PAF1c的影响.
- 研究了基因毒性应激对USP28-53BP1相互作用和USP28二聚体稳定性的影响.
主要成果:
- USP28的二分化限制了它的活动,并限制了MYC介导的PAF1c的招募.
- 单体USP28稳定了MYC,促进了宫外DNA合成和与复制相关的DNA损伤.
- 53BP1结合刺激了USP28的二分化;基因毒性压力破坏了这种相互作用,促进了二分体的分解.
- 压力下USP28二元体的分解刺激MYC介导的PAF1c招募,触发DNA复制原始点火并加剧DNA损伤.
结论:
- USP28二元化作为一个关键的检查点,防止异常DNA在转录活性位点的复制.
- 53BP1-USP28相互作用调节USP28二元稳定性,以应对基因毒性压力.
- 通过控制应激反应期间的DNA复制,USP28二元化对于维持基因组稳定性至关重要.
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