Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai 200240, China.
Nucleic Acids Res. 2024 Jul 22;52(13):7401-7413. doi: 10.1093/nar/gkae502.
Homologous recombination (HR) is a key process for repairing DNA double strand breaks and for promoting genetic diversity. However, HR occurs unevenly across the genome, and certain genomic features can influence its activity. One such feature is the presence of guanine quadruplexes (G4s), stable secondary structures widely distributed throughout the genome. These G4s play essential roles in gene transcription and genome stability regulation. Especially, elevated G4 levels in cells deficient in the Bloom syndrome helicase (BLM) significantly enhance HR at G4 sites, potentially threatening genome stability. Here, we investigated the role of G4-binding protein Yin Yang-1 (YY1) in modulating HR at G4 sites in human cells. Our results show that YY1's binding to G4 structures suppresses sister chromatid exchange after BLM knockdown, and YY1's chromatin occupancy negatively correlates with the overall HR rate observed across the genome. By limiting RAD51 homolog 1 (RAD51) access, YY1 preferentially binds to essential genomic regions, shielding them from excessive HR. Our findings unveil a novel role of YY1-G4 interaction, revealing novel insights into cellular mechanisms involved in HR regulation.
同源重组（HR）是修复 DNA 双链断裂和促进遗传多样性的关键过程。然而，HR 在基因组中不均匀发生，并且某些基因组特征可以影响其活性。这样的特征之一是存在鸟嘌呤四链体（G4s），这是广泛分布在基因组中的稳定的二级结构。这些 G4s 在基因转录和基因组稳定性调节中发挥重要作用。特别是，在 Bloom 综合征解旋酶（BLM）缺陷的细胞中，G4 水平升高会显著增强 G4 位点的 HR，可能威胁基因组稳定性。在这里，我们研究了 G4 结合蛋白 Yin Yang-1（YY1）在调节人类细胞中 G4 位点 HR 中的作用。我们的结果表明，YY1 与 G4 结构的结合抑制了 BLM 敲低后的姐妹染色单体交换，并且 YY1 的染色质占有率与整个基因组中观察到的总体 HR 率呈负相关。通过限制 RAD51 同源物 1（RAD51）的进入，YY1 优先结合到必需的基因组区域，从而防止它们受到过度的 HR。我们的发现揭示了 YY1-G4 相互作用的新作用，揭示了细胞内参与 HR 调节的机制的新见解。
