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SIR2 suppresses replication gaps and genome instability by balancing replication between repetitive and unique sequences

Significance Because the factors required to fire origins of DNA replication are less abundant than the origins themselves, during S phase, these factors are recycled from one area of the genome to another, and, consequently, genome replication occurs in waves. Unique DNA sequences, which contain protein-encoding genes, replicate before repetitive “junk” sequences. By modulating competition for replication resources between these types of sequences, we demonstrate that increased allocation of resources to repetitive sequences, which we previously showed to be associated with reduced lifespan, prevents completion of replication in unique portions of the genome. We suggest that, as cells age, repetitive sequences compete more effectively for replication initiation factors and that the resulting replication gaps form the basis of replicative senescence. Replication gaps that persist into mitosis likely represent important threats to genome stability, but experimental identification of these gaps has proved challenging. We have developed a technique that allows us to explore the dynamics by which genome replication is completed before mitosis. Using this approach, we demonstrate that excessive allocation of replication resources to origins within repetitive regions, induced by SIR2 deletion, leads to persistent replication gaps and genome instability. Conversely, the weakening of replication origins in repetitive regions suppresses these gaps. Given known age- and cancer-associated changes in chromatin accessibility at repetitive sequences, we suggest that replication gaps resulting from misallocation of replication resources underlie age- and disease-associated genome instability.