Foss Eric J, Lao Uyen, Dalrymple Emily, Adrianse Robin L, Loe Taylor, Bedalov Antonio
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
Proc Natl Acad Sci U S A. 2017 Jan 17;114(3):552-557. doi: 10.1073/pnas.1614781114. Epub 2017 Jan 3.
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.
持续到有丝分裂阶段的复制缺口可能对基因组稳定性构成重大威胁，但通过实验鉴定这些缺口颇具挑战性。我们开发了一种技术，能够探究在有丝分裂之前基因组复制得以完成的动态过程。运用该方法，我们证明了由SIR2缺失诱导的、向重复区域内的起始点过度分配复制资源，会导致持续性复制缺口和基因组不稳定。相反，重复区域内复制起始点的弱化则会抑制这些缺口。鉴于已知在重复序列处染色质可及性存在与年龄和癌症相关的变化，我们认为，复制资源分配不当导致的复制缺口是与年龄和疾病相关的基因组不稳定的根本原因。
