The DNA replication process needs to be coordinated with other DNA metabolism transactions and must eventually extend to the full genome, regardless of chromatin status, gene expression, secondary structures and DNA lesions. Completeness and accuracy of DNA replication are crucial to maintain genome integrity, limiting transformation in normal cells and offering targeting opportunities for proliferating cancer cells. DNA replication is thus tightly coordinated with chromatin dynamics and 3D genome architecture, and we are only beginning to understand the underlying molecular mechanisms. While much has recently been discovered on how DNA replication initiation is organised and modulated in different genomic regions and nuclear territories—the so-called “DNA replication program”—we know much less on how the elongation of ongoing replication forks and particularly the response to replication obstacles is affected by the local nuclear organisation. Also, it is still elusive how specific components of nuclear architecture participate in the replication stress response. Here, we review known mechanisms and factors orchestrating replication initiation, and replication fork progression upon stress, focusing on recent evidence linking genome organisation and nuclear architecture with the cellular responses to replication interference, and highlighting open questions and future challenges to explore this exciting new avenue of research.

DNA复制过程需要与其他DNA代谢事务协调，并且最终必须延伸到整个基因组，无论染色质状态、基因表达、二级结构和DNA损伤如何。DNA 复制的完整性和准确性对于维持基因组完整性、限制正常细胞的转化以及为增殖的癌细胞提供靶向机会至关重要。因此，DNA 复制与染色质动力学和 3D 基因组结构紧密协调，我们才刚刚开始了解潜在的分子机制。虽然最近对 DNA 复制起始如何在不同基因组区域和核区域中组织和调节（即所谓的“DNA 复制程序”）有了很多发现，但我们对正在进行的复制叉的延伸，特别是对复制叉的响应知之甚少。复制障碍受到当地核组织的影响。此外，核结构的特定组成部分如何参与复制应激反应仍然难以捉摸。在这里，我们回顾了在压力下协调复制启动和复制叉进展的已知机制和因素，重点关注将基因组组织和核结构与细胞对复制干扰的反应联系起来的最新证据，并强调探索这一令人兴奋的新途径的悬而未决的问题和未来的挑战研究。