SLFN11对抗RFWD3-PRIMPOL DNA损伤耐受性轴,以抑制因复制应激而导致的缺口DNA合成
Kate E Coleman1, Dong-Woo Shin2, Liana Goehring1,2
1Department of Biochemistry & Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, USA.
Nature communications
|December 10, 2025
概括
施莱芬家族成员11 (SLFN11) 抑制DNA复制叉重新启动,防止有效的DNA修复. 这种机制涉及SLFN11对抗RFWD3-PRIMPOL通路,影响DNA损伤耐受性.
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:
- 施莱芬家族成员11 (SLFN11) 的表达使细胞对破坏DNA的化疗敏感.
- 在复制压力期间,SLFN11被招募到停滞的复制叉,但其确切的作用尚不清楚.
研究的目的:
- 为了阐明SLFN11在应力下复制叉中的功能.
- 了解SLFN11影响复制分叉重启和DNA损伤耐受性的机制.
主要方法:
- 单分子DNA纤维分析研究复制叉的动力学.
- 超高分辨率显微镜可视化蛋白质定位在单个复制叉.
- 调查了RFWD3和PRIMPOL在缺少SLFN11的情况下重新启动分叉中的作用.
主要成果:
- 在停滞的分叉上,SLFN11抑制了高效的复制分叉重启.
- 在SLFN11缺乏的细胞中,分叉重新启动是由RFWD3-PRIMPOL途径促进的,用于缺口DNA合成.
- SLFN11通过阻止RFWD3和PRIMPOL招募到停滞的分叉来对抗这种途径,这取决于其ATPase域和定位.
结论:
- SLFN11抑制了RFWD3-PRIMPOL分叉重启路径,从而抵消了DNA损伤耐受性.
- 这提供了关于SLFN11如何影响细胞对复制应激和化疗反应的机制性理解.
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