Preventing excess replication origin activation to ensure genome stability.

Cells activate distinctive regulatory pathways that prevent excessive initiation of DNA replication to achieve timely and accurate genome duplication. Excess DNA synthesis is constrained by protein–DNA interactions that inhibit initiation at dormant origins. In parallel, specific modifications of pre-replication complexes prohibit post-replicative origin relicensing. Replication stress ensues when the controls that prevent excess replication are missing in cancer cells, which often harbor extrachromosomal DNA that can be further amplified by recombination-mediated processes to generate chromosomal translocations. The genomic instability that accompanies excess replication origin activation can provide a promising target for therapeutic intervention. Here we review molecular pathways that modulate replication origin dormancy, prevent excess origin activation, and detect, encapsulate, and eliminate persistent excess DNA. Cells have evolved specialized mechanisms to avoid the deleterious effects of excess initiation from replication origins. During unperturbed proliferation, most potential replication origins are dormant and do not initiate replication but are prepared for activation to facilitate complete genome duplication if cells encounter replication stress. Cells prevent initiation at dormant origins by adjusting chromatin structure to constrain the assembly and activation of pre-replication complexes, targeting components of the replication machinery for degradation or modulating specific protein–DNA interactions at origins. Cancer cells often lack the controls that prevent excess activation of replication origins, resulting in the amplification of extrachromosomal DNA that can persist if they contain genes that can confer a selective growth advantage. Cells activate metabolic and inflammatory responses to sense and encapsulate and eliminate excess DNA. Because excess replication origin activation can directly or indirectly lead to genomic instability, targeting the pathways that prevent excess replication or eliminate excess DNA is a promising avenue for therapeutic intervention. [ABSTRACT FROM AUTHOR]