ADAR1 links R-loop homeostasis to ATR activation in replication stress response.
ADAR1 links R-loop homeostasis to ATR activation in replication stress response.
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DOI：
10.1093/nar/gkad839
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发表时间：
2023-11-27
影响因子：
14.9
通讯作者：
中科院分区：
文献类型：
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作者：
非计划的R-环是复制压力和DNA损伤的主要来源。R-环诱导的复制缺陷被ATR激酶感知和抑制，但尚不清楚R-环本身是否积极参与ATR激活，如果是，这是如何实现的。在这里，我们报告了RNA编辑酶ADAR1的核形式促进ATR激活并解析全基因组R环，这一过程需要其双链RNA结合域。从机制上讲，ADAR1与TOPBP1相互作用，并通过增强TOPBP1与9-1-1复合体的RAD9的结合来促进其在扰动的复制叉上的负载。当复制被抑制时，DNA-RNA杂交物与TOPBP1竞争ADAR1结合，促进ADAR1从受损的叉子转移到R-环区积累。在那里，ADAR1招募RNA解旋酶DHX9和DDX21来解开R环，同时允许TOPBP1更有效地刺激ATR。综上所述，我们认为ADAR1核蛋白复合体的节奏空间调控组装连接了R-环清除和ATR激活，而R-环通过转座ADAR1与被阻断的复制叉串扰，以微调ATR活性和保护基因组。
Unscheduled R-loops are a major source of replication stress and DNA damage. R-loop-induced replication defects are sensed and suppressed by ATR kinase, whereas it is not known whether R-loop itself is actively involved in ATR activation and, if so, how this is achieved. Here, we report that the nuclear form of RNA-editing enzyme ADAR1 promotes ATR activation and resolves genome-wide R-loops, a process that requires its double-stranded RNA-binding domains. Mechanistically, ADAR1 interacts with TOPBP1 and facilitates its loading on perturbed replication forks by enhancing the association of TOPBP1 with RAD9 of the 9–1-1 complex. When replication is inhibited, DNA–RNA hybrid competes with TOPBP1 for ADAR1 binding to promote the translocation of ADAR1 from damaged fork to accumulate at R-loop region. There, ADAR1 recruits RNA helicases DHX9 and DDX21 to unwind R-loops, simultaneously allowing TOPBP1 to stimulate ATR more efficiently. Collectively, we propose that the tempo-spatially regulated assembly of ADAR1-nucleated protein complexes link R-loop clearance and ATR activation, while R-loops crosstalk with blocked replication forks by transposing ADAR1 to finetune ATR activity and safeguard the genome.
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影响因子：
16
作者：
Gong, Zihua;Kim, Ja-Eun;Leung, Charles Chung Yun;Glover, J. N. Mark;Chen, Junjie
通讯作者：
Chen, Junjie
影响因子：
46.9
作者：
Fredriksson, S;Gullberg, M;Landegren, U
通讯作者：
Landegren, U
影响因子：
4
作者：
Desterro, JMP;Keegan, LR;Carmo-Fonseca, M
通讯作者：
Carmo-Fonseca, M
转录复制冲突取向调节R环水平并激活不同的DNA损伤反应。
影响因子：
64.5
作者：
Hamperl S;Bocek MJ;Saldivar JC;Swigut T;Cimprich KA
通讯作者：
Cimprich KA
影响因子：
8.8
作者：
Cristini A;Groh M;Kristiansen MS;Gromak N
通讯作者：
Gromak N