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通过ATR介导的RIPK1酸化抑制了DNA损伤引起的亡

Shen-Nan Shi¹, Qiuyang Xu¹, Xiaofei Jiao¹

¹Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Biochemical pharmacology

|June 25, 2025

概括

ATAXIA telangiectasia和rad3相关蛋白 (ATR) 通过抑制RIPK1.1,抑制卵巢癌中DNA损伤诱导的亡. 针对这种相互作用可能会提高化疗的有效性并改善患者的治疗结果.

科学领域:

分子生物学分子生物学
癌症研究癌症研究
细胞死亡途径细胞死亡途径

背景情况:

化疗期间的DNA损伤可以触发细胞亡,这是一个被编程的细胞死亡途径,为上皮卵巢癌提供治疗策略.
ATAXIA telangiectasia和rad3相关蛋白 (ATR) 是DNA损伤检查点中的关键激酶,调节修复和细胞命运.
精确的ATR影响亡的机制,特别是在DNA损伤的背景下,尚未完全阐明.

研究的目的:

为了研究ATR在调节受体相互作用的氨酸/氨酸蛋白激酶1 (RIPK1) - - 在DNA损伤后依赖性亡的作用.
阐明ATR控制RIPK1激活和亡的分子机制.
确定ATR-RIPK1相互作用对卵巢癌化学敏感性的治疗影响.

主要方法:

使用生物化学测试研究了ATR和RIPK1之间的相互作用.
利用位点定向突变发生 (S335A) 来评估RIPK1被ATR酸化的作用.
在卵巢癌细胞系中使用RIPK1淘汰和补充系统来评估亡和化学敏感性.

主要成果:

ATR直接与RIPK1结合,并通过在Ser335 (S335) 酸化RIPK1来抑制其激活和下游瘤形成.
在RIPK1中S335A突变缓解了ATR介导的抑制,导致增强的亡.
在S335中ATR介导的RIPK1化促进了卵巢癌细胞的化学抵抗,而S335A突变显著增加了化学敏感性,细胞死亡和减少活力.

结论:

在S335处RIPK1的ATR依赖酸化是抑制DNA损伤诱导的亡的关键机制,并在卵巢癌中产生化学抵抗.
针对ATR-RIPK1相互作用,特别是通过防止S335酸化,代表了一种潜在的治疗策略,用于增强亡并改善卵巢癌治疗中的化学敏感性.

关键词:

这是一个ATRATRATRATR.化学敏感性化学敏感性造成的DNA损伤是DNA损伤.尸体灭 (Necroptosis) 是一种死亡的过程.卵巢癌是发生在卵巢中的癌症.在RIPK1中使用.

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