Chromosomal Mcm2-7 distribution is the primary driver of the genome replication program in species from yeast to humans

The spatio-temporal program of genome replication across eukaryotes is thought to be driven both by the uneven loading of pre-replication complexes (pre-RCs) across the genome at the onset of S-phase, and by differences in the timing of activation of these complexes during S- phase. To determine the degree to which distribution of pre-RC loading alone could account for chromosomal replication patterns, we mapped the binding sites of the Mcm2-7 helicase complex (MCM) in budding yeast, fission yeast, mouse and humans. We observed identical individual MCM double-hexamer footprints across the species, but notable differences in their distribution. Nonetheless, most fluctuations in replication timing in all four organisms could be accounted for by differences in chromosomal MCM distribution. We conclude that, although certain genomic regions, most notably the inactive X-chromosome, are subject to post-licensing regulation, most differences in replication timing along the chromosome reflect uneven chromosomal distribution of stochastically firing pre-replication complexes.真核生物全基因组复制的时空程序，被认为由两类因素共同驱动：一是S期起始时全基因组上复制前复合体（pre-RCs）的不均等装载，二是这些复合体在S期内的激活时序差异。为明确仅依靠复制前复合体的装载分布，即可在多大程度上解释染色体复制模式，我们对酿酒酵母、裂殖酵母、小鼠及人类细胞中的Mcm2-7解旋酶复合体（MCM）结合位点进行了定位检测。我们在四个物种中均观测到结构一致的单个MCM双六聚体结合足迹，但这些足迹的分布模式存在显著差异。尽管如此，四个物种中复制时序的绝大多数波动，均可通过染色体上MCM的分布差异得到合理解释。我们最终得出结论：尽管部分基因组区域（最典型的为失活X染色体）存在许可后调控机制，但整条染色体上复制时序的绝大多数差异，均反映了随机激活的复制前复合体在染色体上的不均等分布。