Department of Molecular Biology and Genetics, Aarhus University, C.F. Møllers Allé 3, Building 1130, 8000 Aarhus C, Denmark.
Department of Molecular Biology and Genetics, Aarhus University, C.F. Møllers Allé 3, Building 1130, 8000 Aarhus C, Denmark.
Cell Rep. 2019 Jan 22;26(4):836-844.e3. doi: 10.1016/j.celrep.2018.12.108.
A natural and frequently occurring replication problem is generated by the action of topoisomerase I (Top1). Trapping of Top1 in a cleavage complex on the DNA generates a protein-linked DNA nick (PDN), which upon DNA replication can be transformed into a one-ended double-strand break (DSB). Break-induced replication (BIR) has been recognized as a critical repair mechanism of one-ended DSBs. Here, we have investigated resection at a one-ended DSB formed exclusively during replication due to Top1-mimicking damage. We show that resection is minimal, and only when strand invasion is abolished is extensive resection detected. When DNA synthesis is slowed by hydroxyurea treatment, extended resection is not observed, which suggests that strand invasion and/or heteroduplex formation restrains resection. Our results demonstrate that the BIR pathway acting during S phase is tailored to prevent hazardous effects of naturally and frequently occurring DNA breaks such as Top1-generated PDNs.
拓扑异构酶 I（Top1）的作用会产生一种自然且频繁出现的复制问题。Top1 在 DNA 上形成的断裂复合物会产生一个蛋白连接的 DNA 缺口（PDN），在 DNA 复制时，这个缺口可能会转化为单链断裂（DSB）。断裂诱导复制（BIR）已被认为是单链断裂的关键修复机制。在这里，我们研究了由于 Top1 模拟损伤而仅在复制过程中形成的单链断裂处的切除。我们发现切除很少，只有当链入侵被阻止时，才会检测到广泛的切除。当 DNA 合成因羟基脲处理而减慢时，不会观察到延伸的切除，这表明链入侵和/或异源双链形成抑制了切除。我们的结果表明，在 S 期发挥作用的 BIR 途径是为了防止自然且频繁发生的 DNA 断裂（如 Top1 产生的 PDN）的危险影响而量身定制的。
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