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PARI Regulates Stalled Replication Fork Processing To Maintain Genome Stability upon Replication Stress in Mice

Ayako L Mochizuki1, Ami Katanaya1, Eri Hayashi1

  • 1Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.

Molecular and Cellular Biology
|September 13, 2017
PubMed

Insights

The protein PARI is crucial for maintaining genome stability in mice by managing DNA replication stress. It helps prevent chromosome instability, particularly in pluripotent stem cells facing internal or external damage.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • DNA replication is vital for genome integrity but is susceptible to various stresses.
  • Proper coordination between DNA replication and repair is essential at damaged replication forks.
  • The role of specific proteins in managing replication stress requires further elucidation.

Purpose of the Study:

  • To investigate the role of the PARI antirecombinase in the response to replication stress in mice.
  • To understand how PARI modulates DNA replication and repair dynamics at stalled forks.
  • To determine the physiological significance of PARI in maintaining chromosome stability.

Main Methods:

  • Studied the function of PARI in mouse models and embryonic stem cells.
  • Analyzed the effects of PARI on nascent-strand shortening, double-strand break induction, and origin firing.
  • Assessed chromosome stability in wild-type and Pari-deficient cells under replication stress conditions.

Main Results:

  • PARI is dormant during normal replication but becomes active under replication stress.
  • Activated PARI enhances nascent-strand shortening regulated by RAD51 and MRE11.
  • PARI promotes double-strand break induction and new origin firing, rather than replication restart.
  • Pari-deficient cells exhibit spontaneous chromosome instability, especially in pluripotent stem cells.

Conclusions:

  • PARI is a critical regulator of stalled fork processing, essential for genome stability under replication stress.
  • PARI's function, though seemingly obstructive to replication, is physiologically required for chromosome stability in mice.
  • Pluripotent stem cells have a heightened requirement for PARI to counteract endogenous replication stress.
Keywords:
embryonic stem cellsgenome stabilityhomologous recombinationreplication stress

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