Hyrien Olivier, Guilbaud Guillaume, Krude Torsten
Département de Biologie, École Normale Supérieure, Université Paris Science and Letters, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut de Biologie de l'Ecole Normale Superieure, 75005 Paris, France.
Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom.
Genes Dev. 2025 Mar 3;39(5-6):304-324. doi: 10.1101/gad.352227.124.
Mammalian DNA replication origins have been historically difficult to identify and their determinants are still unresolved. Here, we first review methods developed over the last decades to map replication initiation sites either directly via initiation intermediates or indirectly via determining replication fork directionality profiles. We also discuss the factors that may specify these sites as replication initiation sites. Second, we address the controversy that has emerged from these results over whether origins are narrowly defined and localized to specific sites or are more dispersed and organized into broad zones. Ample evidence in favor of both scenarios currently creates an impression of unresolved confusion in the field. We attempt to formulate a synthesis of both models and to reconcile discrepant findings. It is evident that not only one approach is sufficient in isolation but that the combination of several is instrumental toward understanding initiation sites in mammalian genomes. We argue that an aggregation of several individual and often inefficient initiation sites into larger initiation zones and the existence of efficient unidirectional initiation sites and fork stalling at the borders of initiation zones can reconcile the different observations.
长期以来，哺乳动物DNA复制起点一直难以确定，其决定因素仍未得到解决。在这里，我们首先回顾过去几十年中开发的方法，这些方法要么通过起始中间体直接绘制复制起始位点，要么通过确定复制叉方向性图谱间接绘制。我们还讨论了可能将这些位点指定为复制起始位点的因素。其次，我们讨论了这些结果引发的争议，即复制起点是被狭义定义并局限于特定位点，还是更分散并组织成广泛区域。目前，支持这两种情况的充分证据给该领域留下了尚未解决的混乱印象。我们试图对这两种模型进行综合，并调和相互矛盾的发现。很明显，仅靠一种方法是不够的，几种方法的结合有助于理解哺乳动物基因组中的起始位点。我们认为，几个单独且通常效率不高的起始位点聚集形成更大的起始区域，以及高效单向起始位点的存在和在起始区域边界处的叉停滞，可以调和不同的观察结果。
