Liu Yang, Zhangding Zhengrong, Liu Xuhao, Gan Tingting, Ai Chen, Wu Jinchun, Liang Haoxin, Chen Mohan, Guo Yuefeng, Lu Rusen, Jiang Yongpeng, Ji Xiong, Gao Ning, Kong Daochun, Li Qing, Hu Jiazhi
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Genome Editing Research Center, Peking University; Beijing 100871, China.
PKU-THU Center for Life Sciences, Peking University, Beijing 100871, China.
Science. 2024 Mar 15;383(6688):1215-1222. doi: 10.1126/science.adj7606. Epub 2024 Mar 14.
DNA replication is initiated at multiple loci to ensure timely duplication of eukaryotic genomes. Sister replication forks progress bidirectionally, and replication terminates when two convergent forks encounter one another. To investigate the coordination of replication forks, we developed a replication-associated in situ HiC method to capture chromatin interactions involving nascent DNA. We identify more than 2000 fountain-like structures of chromatin contacts in human and mouse genomes, indicative of coupling of DNA replication forks. Replication fork interaction not only occurs between sister forks but also involves forks from two distinct origins to predetermine replication termination. Termination-associated chromatin fountains are sensitive to replication stress and lead to coupled forks-associated genomic deletions in cancers. These findings reveal the spatial organization of DNA replication forks within the chromatin context.
DNA复制在多个位点起始，以确保真核生物基因组的及时复制。姐妹复制叉双向推进，当两个相向的复制叉相遇时复制终止。为了研究复制叉的协调机制，我们开发了一种与复制相关的原位HiC方法，以捕获涉及新生DNA的染色质相互作用。我们在人类和小鼠基因组中鉴定出2000多个类似喷泉状的染色质接触结构，这表明DNA复制叉之间存在耦合。复制叉相互作用不仅发生在姐妹复制叉之间，还涉及来自两个不同起始位点的复制叉，从而预先确定复制终止。与终止相关的染色质喷泉对复制应激敏感，并导致癌症中与耦合复制叉相关的基因组缺失。这些发现揭示了染色质环境中DNA复制叉的空间组织。
