DNA polymerase ε harmonizes topological states and R-loops formation to maintain genome integrity in Arabidopsis.
DNA polymerase ε harmonizes topological states and R-loops formation to maintain genome integrity in Arabidopsis.
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DOI：
10.1038/s41467-023-43680-7
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发表时间：
2023-11-27
影响因子：
16.6
通讯作者：
Sun, Qianwen
中科院分区：
文献类型：
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作者：
Li, Qin;Zhou, Jincong;Li, Shuai;Zhang, Weifeng;Du, Yingxue;Li, Kuan;Wang, Yingxiang;Sun, Qianwen
基因组拓扑结构与R环形成和基因组稳定性有关。然而，监管机制仍有待阐明。通过建立一个系统来检测R环和基因组拓扑状态之间的联系，我们发现，抑制DNA拓扑异构酶1（TOP1i）触发了R环（称为topoR环）和DNA损伤的全球增加，这在DNA损伤修复受损突变体atm中加剧。抑制筛选鉴定了DNA聚合酶ε的催化亚基POL2A中的突变，拯救了TOP1i诱导的topoR环积累和atm中的基因组不稳定性。重要的是，我们发现POL2A中的核酸外切酶和聚合酶结构域之间的高度保守的连接结构域是调节DNA复制起点附近的拓扑环和促进忠实的DNA复制所必需的。我们的研究结果表明，DNA复制与基因组拓扑状态相一致，以微调R环，从而保持基因组的完整性，揭示了ATM缺陷癌症化疗中TOP1i抗性的可能保守调控机制。在这里，作者表明，抑制DNA拓扑异构酶1（TOP1i）增加了DNA损伤修复受损突变体atm的根生长缺陷。他们发现了一种突变的DNA聚合酶ε（POL2A），它通过调节DNA复制起点附近的R环动力学来挽救atm对TOP1i的敏感性。
Genome topology is tied to R-loop formation and genome stability. However, the regulatory mechanism remains to be elucidated. By establishing a system to sense the connections between R-loops and genome topology states, we show that inhibiting DNA topoisomerase 1 (TOP1i) triggers the global increase of R-loops (called topoR-loops) and DNA damages, which are exacerbated in the DNA damage repair-compromised mutant atm. A suppressor screen identifies a mutation in POL2A, the catalytic subunit of DNA polymerase ε, rescuing the TOP1i-induced topoR-loop accumulation and genome instability in atm. Importantly we find that a highly conserved junction domain between the exonuclease and polymerase domains in POL2A is required for modulating topoR-loops near DNA replication origins and facilitating faithful DNA replication. Our results suggest that DNA replication acts in concert with genome topological states to fine-tune R-loops and thereby maintain genome integrity, revealing a likely conserved regulatory mechanism of TOP1i resistance in chemotherapy for ATM-deficient cancers. Here the authors show that Inhibition of DNA topoisomerase 1 (TOP1i) increases the defects in root growth of a DNA damage repair-compromised mutant atm. They identify a mutant DNA polymerase ε (POL2A) which rescues the sensitivity of atm to TOP1i by modulating R-loops dynamics near DNA replication origins.
DNA聚合酶ε与SUVH2/9相互作用抑制拟南芥减数分裂DSB热点相关基因的表达
DOI：
10.1073/pnas.2208441119
发表时间：
2022-10-11
影响因子：
11.1
作者：
通讯作者：
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DOI：
10.1073/pnas.2119588119
发表时间：
2022-03-22
影响因子：
11.1
作者：
Zhang K;Sui Y;Li WL;Chen G;Wu XC;Kokoska RJ;Petes TD;Zheng DQ
通讯作者：
Zheng DQ