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Mre11 exonuclease activity promotes irreversible mitotic progression under replication stress

Yoshitami Hashimoto1, Hirofumi Tanaka2

  • 1School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan hashimo@toyaku.ac.jp.

Life Science Alliance
|March 16, 2022
PubMed

Insights

Mre11 exonuclease activity is crucial for mitotic entry during replication stress. It processes stalled forks, preventing mitotic CDK inactivation and ensuring cell cycle progression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • DNA Replication and Repair

Background:

  • Mre11 is a key enzyme in DNA double-strand break (DSB) processing and checkpoint activation.
  • Replication forks can stall under replication stress, posing a threat to genome stability.
  • Previous work showed forced mitotic entry causes replisome disassembly at stalled forks in Xenopus egg extracts.

Purpose of the Study:

  • To investigate the role of Mre11 exonuclease activity in mitotic entry under replication stress.
  • To elucidate the mechanism by which Mre11 influences mitotic progression when replication forks are stalled.

Main Methods:

  • Utilized a Xenopus egg extract system with forced mitotic entry.
  • Employed chemical inhibitors to examine the effects on Mre11 activity and mitotic progression.
  • Investigated the role of Wee1/Myt1 phosphorylation and CDK1 activity.

Main Results:

  • Mre11 exonuclease activity is essential for initiating mitotic entry when replication forks are stalled.
  • Loss of Mre11 activity leads to mitotic CDK inactivation via Wee1/Myt1 phosphorylation, causing mitotic exit.
  • Inhibiting Wee1/Myt1 or using a nonphosphorylatable CDK1 mutant partially rescues the Mre11-deficient phenotype.

Conclusions:

  • Mre11 exonuclease activity processes stalled replication forks during mitotic entry.
  • This processing attenuates inhibitory pathways, allowing for irreversible mitotic progression and replisome disassembly.
  • Highlights a novel role for Mre11 in maintaining cell cycle integrity under replication stress.

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