The replication checkpoint protects fork stability by releasing transcribed genes from nuclear pores.
The replication checkpoint protects fork stability by releasing transcribed genes from nuclear pores.
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DOI：
10.1016/j.cell.2011.06.033
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发表时间：
2011-07-22
期刊：
影响因子：
64.5
通讯作者：
Foiani M
中科院分区：
文献类型：
--
作者：
Bermejo R;Capra T;Jossen R;Colosio A;Frattini C;Carotenuto W;Cocito A;Doksani Y;Klein H;Gómez-González B;Aguilera A;Katou Y;Shirahige K;Foiani M
转录阻碍了复制叉的进展和稳定性，Mec 1/ATR检查点保护了复制叉的完整性。检查检查点依赖的机制控制叉的稳定性，我们发现，叉逆转和休眠的起源发射由于检查点缺陷被救出检查点突变体缺乏THO，TREX-2，或内篮核孔蛋白。基因门控将基因转录到核外围，并通过核孔蛋白（如Mlp 1）的磷酸化被检查点激酶抵消。检查点突变体不能将转录的基因从核孔中分离出来，从而为进入的分叉产生拓扑障碍。通过在分叉和转录单位之间引入双链断裂来释放这种拓扑复杂性，可以防止分叉崩溃。mlp 1突变体模仿组成性检查点依赖性磷酸化也减轻检查点缺陷。我们建议，检查点协助叉的进展和稳定性，在转录基因的磷酸化关键核孔蛋白和抵消基因门控，从而中和核孔门控基因产生的拓扑张力。<$基因门控失活抑制检查点突变体中的叉崩溃<$Mec1检查点从核孔复合物中释放转录的染色质<$Mec1磷酸化Mlp 1核孔蛋白以释放门控基因处的拓扑块<$通过双链断裂形成释放局部拓扑结构抵消叉崩溃
Transcription hinders replication fork progression and stability, and the Mec1/ATR checkpoint protects fork integrity. Examining checkpoint-dependent mechanisms controlling fork stability, we find that fork reversal and dormant origin firing due to checkpoint defects are rescued in checkpoint mutants lacking THO, TREX-2, or inner-basket nucleoporins. Gene gating tethers transcribed genes to the nuclear periphery and is counteracted by checkpoint kinases through phosphorylation of nucleoporins such as Mlp1. Checkpoint mutants fail to detach transcribed genes from nuclear pores, thus generating topological impediments for incoming forks. Releasing this topological complexity by introducing a double-strand break between a fork and a transcribed unit prevents fork collapse. Mlp1 mutants mimicking constitutive checkpoint-dependent phosphorylation also alleviate checkpoint defects. We propose that the checkpoint assists fork progression and stability at transcribed genes by phosphorylating key nucleoporins and counteracting gene gating, thus neutralizing the topological tension generated at nuclear pore gated genes. ► Gene gating inactivation suppresses fork collapse in checkpoint mutants ► The Mec1 checkpoint releases transcribed chromatin from nuclear pore complexes ► Mec1 phosphorylates Mlp1 nucleoporin to release topological blocks at gated genes ► Releasing local topology by double-strand break formation counteracts fork collapse
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影响因子：
21.3
作者：
Feng, Wenyi;Collingwood, David;Boeck, Max E;Fox, Lindsay A;Alvino, Gina M;Fangman, Walton L;Raghuraman, Mosur K;Brewer, Bonita J
通讯作者：
Brewer, Bonita J
影响因子：
9.8
作者：
Brickner DG;Cajigas I;Fondufe-Mittendorf Y;Ahmed S;Lee PC;Widom J;Brickner JH
通讯作者：
Brickner JH
影响因子：
--
作者：
Drubin, David A.;Garakani, Arman M.;Silver, Pamela A.
通讯作者：
Silver, Pamela A.
影响因子：
10.5
作者：
Bermejo, Rodrigo;Branzei, Dana;Foiani, Marco
通讯作者：
Foiani, Marco
影响因子：
5.3
作者：
Gomez-Gonzalez, Belen;Felipe-Abrio, Irene;Aguilera, Andres
通讯作者：
Aguilera, Andres