title: SIR2 suppresses replication gaps and genome instability by balancing replication between repetitive and unique sequences.
abstract: 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.
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Foss
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors.forename: Uyen
authors.initials: U
authors.lastname: Lao
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors.forename: Emily
authors.initials: E
authors.lastname: Dalrymple
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Adrianse
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors.forename: Taylor
authors.initials: T
authors.lastname: Loe
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; abedalov@fredhutch.org.|Department of Medicine, University of Washington, Seattle, WA 98195.|Department of Biochemistry, University of Washington, Seattle, WA 98195.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bedalov
mesh_terms: D015825:Chromosomes, Fungal / Q000235:genetics; D004261:DNA Replication; D004271:DNA, Fungal / Q000096:biosynthesis / Q000235:genetics; D004275:DNA, Ribosomal / Q000096:biosynthesis / Q000235:genetics; D017353:Gene Deletion; D016681:Genome, Fungal; D042822:Genomic Instability; D006801:Humans; D008954:Models, Biological; D012091:Repetitive Sequences, Nucleic Acid; D018741:Replication Origin; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056565:Sirtuin 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D004271:DNA, Fungal; D004275:DNA, Ribosomal; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2
keywords: DNA replication; SIR2; repetitive sequences; replication gaps; ribosomal DNA