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梅尼因的Fyn介导酸化扰乱了干细胞中的端粒维护

Souren Paul¹, Preston M McCourt¹, Le Thi My Le¹

¹The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.

bioRxiv : the preprint server for biology

|October 24, 2023

概括

Src家族基因酶Fyn通过酸化Menin来破坏干细胞端粒维护,影响端粒酶的功能. 抑制Fyn可以保持端粒长度,为相关遗传疾病提供潜在的治疗策略.

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:

端粒保护染色体末端,并由干细胞中的端粒酶维持.
调节端粒酶活性和端粒长度的机制尚未完全理解.
遗传性失色症与影响端粒维护的突变有关.

研究的目的:

研究Src家族激酶Fyn在干细胞中端粒维持中的作用.
阐明Fyn影响端粒酶功能的分子机制.
探索Fyn抑制作为与端粒相关疾病的治疗方法.

主要方法:

在人类和小鼠的干细胞中利用Fyn敲击和抑制.
为了验证,采用了四种不同的端粒测量技术.
进行了质谱,免疫沉和免疫光测试.
研究了Fyn对Menin酸化,SUMO1修饰和蛋白质与蛋白质相互作用的影响.

主要成果:

这种Fyn knockdown可以防止干细胞中的端粒侵蚀.
在Y603处的Fyn酸化Menin,增加SUMO1的修饰和与端粒酶RNA (TR) 的关联.
SUMO1-Menin减少了TR与Dyskerin的关联,导致端粒酶亚单元的错位化和潜在的功能障碍.
在人类iPSCs中,Fyn抑制改善了患有先天性硬瘤突变的加速端粒缩短.

结论:

Src家族基因酶Fyn在干细胞中破坏端粒维护方面发挥着关键作用.
通过Fyn介导的Menin酸化通过改变的子单元协会损害了端粒酶的功能.
针对Fyn是一个有希望的策略,可以在特定遗传条件下抵消加速的端粒缩短.

关键词:

遗传性肌肉变质症 (Dyskeratosis Congenita) 是一种与生俱来的疾病.菲恩 (Fyn Fyn) 是一个很好的地方.梅宁是什么意思梅宁是什么意思干细胞是一种干细胞.泰洛米尔 (Telomere) 是一种电离体.

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