Figure 2, Key figure. Replication origins and excess replication.

Top panel: Potential replication origins are licensed in excess. The distribution of licensed origins throughout the genome varies based on chromatin marks, gene density, replication timing and other restrictions on nuclear organization. Pre-RCs, which are a prerequisite for DNA replication, are first nucleated by the assembly of six ORC proteins (ORC1-6) onto chromatin. CDC6 then binds the ORC complex to form a ring-shaped complex that will recruit, together with CDT1, several heterohexamers of the six MCM proteins (MCM2-7) (top panel). Middle panel: During normal unperturbed replication, only a small fraction of licensed origins is activated with most licensed origins remaining dormant. These dormant origins are then passively replicated with pre-RCs subunits being dismantled, degraded or recycled to avoid re-licensing during S phase. Inhibition of dormant origin activation may be facilitated by SIRT1. Bottom panel: Two different pathways can result in over-replication. The first pathway, dormant origin activation, can occur during replication stress through ATR/CHK1 mediated phosphorylation or due to the loss of a protein SIRT1, which is involved in dormant origin silencing. The second pathway, DNA re-replication, occurs when origins are re-licensed during S phase before DNA replication is completed and can be triggered by inhibition of pre-RC component degradation, chromatin decondensation or oncogene over-expression. Both pathways could lead to DNA damage and genomic instability, leading to senescence or tumor progression.