TY - JOUR
T1 - The replication checkpoint protects fork stability by releasing transcribed genes from nuclear pores
AU - Bermejo, Rodrigo
AU - Capra, Thelma
AU - Jossen, Rachel
AU - Colosio, Arianna
AU - Frattini, Camilla
AU - Carotenuto, Walter
AU - Cocito, Andrea
AU - Doksani, Ylli
AU - Klein, Hannah
AU - Gómez-González, Belén
AU - Aguilera, Andrés
AU - Katou, Yuki
AU - Shirahige, Katsuhiko
AU - Foiani, Marco
PY - 2011/7/22
Y1 - 2011/7/22
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2011.06.033
DO - 10.1016/j.cell.2011.06.033
M3 - Article
C2 - 21784245
AN - SCOPUS:79960802984
VL - 146
SP - 233
EP - 246
JO - Cell
JF - Cell
SN - 0092-8674
IS - 2
ER -