rereplication

Rereplication, or re-replication, is a cellular phenomenon in which portions of the genome are replicated more than once within a single cell cycle. This occurs when DNA replication origins that were fired in S phase reinitiate before mitosis, producing DNA over-replication and genome instability. In normal cells, origins are licensed in G1 and fired once during S phase; licensing factors are then removed or inhibited to prevent a second round of initiation.

Mechanistically, DNA replication licensing involves origin recognition complex (ORC), Cdc6, and Cdt1 to license origins, with geminin acting as an inhibitor of Cdt1 to prevent re-licensing during S, G2, and M phases. After replication, licensing factors are degraded or inactivated. If this control is perturbed—by overexpression of Cdt1 or Cdc6, loss of geminin, or improper CDK activity—origins can fire again within the same cycle, leading to rereplication.

Consequences of rereplication include replication stress and DNA damage, activation of DNA damage response pathways (such as ATR/ATM), and accumulation of double-strand breaks. Cells may arrest, undergo apoptosis or senescence, or in some contexts contribute to genomic instability and tumorigenesis through copy number variations and aneuploidy.

Causes are typically disruptions of replication licensing controls, including regulatory protein imbalances, mutations, or experimental manipulations that disrupt the normal licensing checkpoint. Detection methods in experimental systems include flow cytometry showing DNA content beyond 4N, genome-wide copy number analyses, and markers of replication stress (for example, γ-H2AX) alongside assays that reveal reinitiation events.

Rereplication is a focus of study in cell cycle regulation and cancer biology, where failures in licensing safeguards can promote genomic instability and influence tumor development and progression.