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在PRMT1-介导的DNA修复和白血病进展中ATG4B的非正规作用

Zhenkun Wang¹, Yuting Fu¹, Shuyi Lin¹

¹Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China.

|September 19, 2025

概括

在代谢压力下,与自相关的4B (ATG4B) 进入细胞核,通过分裂PRMT1损害DNA修复,并促进急性髓性白血病 (AML) 的进展. 在AML细胞中抑制ATG4B可以恢复DNA修复并延缓白血病.

科学领域:

分子生物学分子生物学
细胞生物学细胞生物学
癌症研究癌症研究

背景情况:

自相关 (ATG) 蛋白质在自之外具有非正规的功能,特别是在不同的亚细胞区.
特别是在代谢压力下,ATG4B (自相关的4B,囊酶) 的非正规作用在很大程度上尚未被探索.
在自中ATG4B的正规作用包括裂解MAP1LC3/LC3和PE,这对于自细胞形成至关重要.

研究的目的:

为了研究ATG4B在代谢压力下非正规的,自独立的功能.
阐明核ATG4B影响DNA修复的机制.
评估ATG4B作为急性髓性白血病 (AML) 的潜在治疗点.

主要方法:

研究了ATG4B通过能量剥夺引起的核转移.
研究了ATG4B和PRMT1 (蛋白质氨酸甲基转移酶1) 在核中的相互作用.
评估了ATG4B对PRMT1介导的MRE11甲基化和随后的DNA修复能力的影响.
在AML细胞中利用了ATG4B的基因淘汰和药理抑制.
在AML模型中监测DNA修复,CHEK1/CHK1激活和恶性进展.

主要成果:

能源剥夺触发了ATG4B的自独立的核积累.
核ATG4B分裂PRMT1,减少MRE11甲基化,并影响DNA修复.
在AML细胞的细胞核中,ATG4B被上调并积累.
在AML细胞中抑制ATG4B可以恢复DNA修复,激活CHEK1/CHK1并减轻白血病的进展.

结论:

核ATG4B在将代谢压力与DNA修复抑制联系起来时,扮演着自独立的角色.
ATG4B的核功能有助于AML恶性进展.
在AML治疗中,ATG4B是一个有前途的治疗标.

关键词:

在ATG4B中,它是ATG4B.修复DNA的修复DNA的修复在PRMT1中,能量代谢能量代谢这种白血病是白血病.

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