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ASPM promotes ATR-CHK1 activation and stabilizes stalled replication forks in response to replication stress

Xingxuan Wu1,2,3, Shibin Xu1,4, Peipei Wang1

  • 1The Sixth Affiliated Hospital of Shenzhen University, Guangdong Key Laboratory for Genome Stability and Disease Prevention and Carson International Cancer Center, Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen 518060, China.

Proceedings of the National Academy of Sciences of the United States of America
|September 26, 2022
PubMed

Insights

ASPM protein is crucial for DNA replication stress response, aiding in stalled fork repair and genome stability. Its depletion causes chromosome instability and sensitizes cancer cells to replication stressors.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • ASPM (microcephaly protein 5) is vital for mitosis and neural stem cell division.
  • ASPM was previously shown to promote homologous recombination (HR) DNA repair.
  • The role of ASPM in DNA replication and its response to replication stress was unknown.

Purpose of the Study:

  • To investigate the function of ASPM in DNA replication and replication stress response.
  • To elucidate the mechanism by which ASPM influences genome stability under replication stress.

Main Methods:

  • Cellular assays to assess DNA replication under normal and stressed conditions.
  • Analysis of ASPM localization at replication forks.
  • Investigating the interaction of ASPM with key DNA repair and checkpoint proteins (RAD17, RAD9, TopBP1, ATR-CHK1).
  • Assessing the impact of ASPM depletion on replication fork restart and DNA degradation.

Main Results:

  • ASPM is not essential for DNA replication in unperturbed conditions.
  • ASPM localizes to stalled replication forks in a RAD17-dependent manner.
  • ASPM facilitates the loading of RAD9 and TopBP1, promoting ATR-CHK1 activation.
  • ASPM depletion leads to failed replication fork restart and MRE11-mediated DNA degradation.
  • ASPM deficiency results in chromosome instability and increased sensitivity of cancer cells to replication stress.

Conclusions:

  • ASPM plays a critical role in the DNA replication stress response pathway.
  • ASPM functions by facilitating the recruitment of key checkpoint proteins to stalled replication forks.
  • These findings highlight ASPM's importance in maintaining genome stability and suggest potential therapeutic targets in cancer.
Keywords:
ATR-CHK1DNA replicationprimary microcephalyreplication stress

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