Nguyen Alexandra L, Smith Eric M, Cheeseman Iain M
Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Dev Cell. 2025 Apr 21;60(8):1217-1233.e7. doi: 10.1016/j.devcel.2024.12.015. Epub 2024 Dec 31.
The cohesin complex is critical for genome organization and regulation, relying on specialized co-factors to mediate its diverse functional activities. Here, by analyzing patterns of similar gene requirements across cell lines, we identify PRR12 as a mediator of cohesin and genome integrity. We show that PRR12 interacts with NIPBL/MAU2 and the cohesin complex, and that the loss of PRR12 results in reduced cohesin localization and a substantial increase in DNA double-strand breaks in mouse NIH-3T3 cells. Additionally, PRR12 co-localizes with NIPBL to sites of DNA damage in a NIPBL and cohesin-dependent manner. We find that the requirement for PRR12 differs across cell lines, with human HeLa cells exhibiting reduced sensitivity to PRR12 loss compared with mouse NIH-3T3 cells, indicating context-specific roles. Together, our work identifies PRR12 as a regulator of cohesin and provides insight into how genome integrity is maintained across diverse cellular contexts.
黏连蛋白复合体对于基因组的组织和调控至关重要，它依赖于特定的辅助因子来介导其多样的功能活动。在此，通过分析跨细胞系的相似基因需求模式，我们鉴定出PRR12是黏连蛋白和基因组完整性的介导因子。我们表明PRR12与NIPBL/MAU2及黏连蛋白复合体相互作用，并且PRR12的缺失会导致黏连蛋白定位减少以及小鼠NIH-3T3细胞中DNA双链断裂大幅增加。此外，PRR12以依赖NIPBL和黏连蛋白的方式与NIPBL共定位于DNA损伤位点。我们发现不同细胞系对PRR12的需求不同，与小鼠NIH-3T3细胞相比，人类HeLa细胞对PRR12缺失的敏感性降低，这表明其具有细胞背景特异性作用。总之，我们的工作鉴定出PRR12是黏连蛋白的调节因子，并为在不同细胞背景下如何维持基因组完整性提供了见解。
