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Replication stress induces mitotic death through parallel pathways regulated by WAPL and telomere deprotection

V Pragathi Masamsetti1, Ronnie Ren Jie Low1,2,3, Ka Sin Mak1

  • 1Children's Medical Research Institute, University of Sydney, Westmead, NSW, 2145, Australia.

Nature Communications
|September 19, 2019
PubMed

Insights

Replication stress causes cell death via two pathways: one involving centromere defects and apoptosis, the other telomere deprotection. Understanding these mechanisms is key for cancer treatment.

Area of Science:

  • Cell biology
  • Molecular oncology
  • Genetics

Background:

  • Mitotic catastrophe is a poorly understood cell death mechanism.
  • Replication stress is a known cellular insult with unclear downstream effects on mitosis.

Purpose of the Study:

  • To investigate the mechanisms of replication stress-induced mitotic catastrophe in human cells.
  • To identify the distinct cell death pathways activated by replication stress.

Main Methods:

  • Analysis of p53-compromised human cells undergoing replication stress.
  • Investigation of centromere cohesion, spindle assembly checkpoint, apoptosis (BAX/BAK), and telomere deprotection (TRF2, Aurora B, ATM).

Main Results:

  • Replication stress induces mitotic death through two independent pathways.
  • Pathway 1: WAPL-dependent cohesion defects lead to mitotic arrest and BAX/BAK-dependent apoptosis.
  • Pathway 2: Non-canonical telomere deprotection involving TRF2, Aurora B, and ATM.

Conclusions:

  • Replication stress triggers distinct cell death signaling routes, contributing to mitotic catastrophe.
  • Targeting these pathways offers potential for cancer therapy and understanding cancer genome evolution.

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