Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Human Phenome Institute, Fudan University, Shanghai, China.
Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
Nature. 2023 Sep;621(7979):610-619. doi: 10.1038/s41586-023-06515-5. Epub 2023 Aug 9.
The proper regulation of transcription is essential for maintaining genome integrity and executing other downstream cellular functions. Here we identify a stable association between the genome-stability regulator sensor of single-stranded DNA (SOSS) and the transcription regulator Integrator-PP2A (INTAC). Through SSB1-mediated recognition of single-stranded DNA, SOSS-INTAC stimulates promoter-proximal termination of transcription and attenuates R-loops associated with paused RNA polymerase II to prevent R-loop-induced genome instability. SOSS-INTAC-dependent attenuation of R-loops is enhanced by the ability of SSB1 to form liquid-like condensates. Deletion of NABP2 (encoding SSB1) or introduction of cancer-associated mutations into its intrinsically disordered region leads to a pervasive accumulation of R-loops, highlighting a genome surveillance function of SOSS-INTAC that enables timely termination of transcription at promoters to constrain R-loop accumulation and ensure genome stability.
转录的适当调控对于维持基因组完整性和执行其他下游细胞功能至关重要。在这里，我们发现基因组稳定性调节剂单链 DNA 传感器（SOSS）和转录调节剂整合体-PP2A（INTAC）之间存在稳定的关联。通过 SSB1 介导的单链 DNA 识别，SOSS-INTAC 刺激转录的启动子近端终止，并减弱与暂停 RNA 聚合酶 II 相关的 R 环，以防止 R 环诱导的基因组不稳定性。SSB1 形成液态凝聚物的能力增强了 SOSS-INTAC 依赖性 R 环的衰减。SSB1（编码 SSB1）的缺失或其无规卷曲区域中致癌相关突变的引入导致 R 环的普遍积累，突出了 SOSS-INTAC 的基因组监测功能，使转录在启动子处及时终止，从而限制 R 环的积累并确保基因组稳定性。
