The Replication Checkpoint Protects Fork Stability by Releasing Transcribed Genes from Nuclear Pores


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.

DOI: 10.1016/j.cell.2011.06.033

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@inproceedings{Bermejo2011TheRC, title={The Replication Checkpoint Protects Fork Stability by Releasing Transcribed Genes from Nuclear Pores}, author={Rodrigo Bermejo and Thelma Capra and Rachel Jossen and Arianna Colosio and Camilla Frattini and Walter Vincenzo Carotenuto and Andrea Cocito and Ylli Doksani and Hannah L. Klein and Bel{\'e}n G{\'o}mez-Gonz{\'a}lez and Andr{\'e}s Ram{\'i}rez Aguilera and Yuki Katou and Katsuhiko Shirahige and Marco Foiani}, booktitle={Cell}, year={2011} }