rereplicating

Rereplication refers to the initiation of DNA synthesis at origins more than once during a single cell cycle, producing regions of DNA that have been replicated multiple times. In normal eukaryotic replication, each origin fires once in S phase after origins are licensed in G1 and then passively replicated. Rereplication arises when the licensing and firing controls fail to restrict replication to a single event per cycle, creating locally amplified DNA content and genomic instability.

Mechanistically, origin licensing involves loading the MCM2-7 helicase complex onto DNA at origins during G1, a process driven by ORC, Cdc6, and Cdt1. This licensing marks origins for potential firing in S phase when CDK and DDK activities promote origin opening and DNA synthesis. Normally, once replication begins, licensing is inhibited to prevent re-loading of MCM2-7 and re-firing within the same cycle. Deregulation can occur through overexpression of licensing factors such as Cdt1 or Cdc6, loss or inhibition of the licensing inhibitor geminin, or abnormal CDK activity, allowing a subset of origins to re-license and initiate additional rounds of replication.

Consequences of rereplication include replication fork stalling and collisions, DNA strand breaks, and activation of the DNA damage response. Cells may arrest, enter senescence, or undergo apoptosis, depending on the extent of rereplication and the integrity of surveillance pathways. Rereplication contributes to genome instability and copy number variation and is studied as a model for understanding replication licensing, DNA damage responses, and the mechanisms underlying oncogenic genome amplification.