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Inhibition of homologous recombination by the PCNA-interacting protein PARI

George-Lucian Moldovan1, Donniphat Dejsuphong, Mark I R Petalcorin

  • 1Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Molecular Cell
|December 14, 2011
PubMed

Insights

Human cells utilize PARI protein to prevent genomic instability by limiting DNA repair via homologous recombination (HR) at replication forks. PARI

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Inappropriate homologous recombination (HR) is a significant driver of genomic instability and cancer development.
  • In yeast, the Srs2 helicase, recruited by SUMO-modified PCNA, disassembles RAD51 nucleofilaments to restrict HR at replication forks.
  • Mechanisms controlling HR at human replication forks remain largely uncharacterized.

Purpose of the Study:

  • To identify and characterize human proteins that regulate homologous recombination (HR) at DNA replication forks.
  • To investigate the role of the protein PARI in maintaining genome stability and suppressing unscheduled recombination.

Main Methods:

  • Utilized cell-based assays and biochemical experiments to study PARI function.
  • Investigated PARI's interaction with PCNA (proliferating cell nuclear antigen).
  • Assessed PARI's effect on RAD51-DNA structure formation and genomic instability in various cell types, including Fanconi Anemia/BRCA pathway-deficient cells.

Main Results:

  • Identified PARI, a protein with a UvrD-like helicase domain, as a PCNA-interacting partner crucial for genome stability in human and chicken cells.
  • Demonstrated that PARI actively restricts unscheduled homologous recombination (HR) by preventing the formation of RAD51-DNA structures.
  • Showed that PARI depletion exacerbates genomic instability in cells deficient in the Fanconi Anemia/BRCA pathway.

Conclusions:

  • PARI functions as a key regulator suppressing inappropriate homologous recombination (HR) at mammalian replication forks.
  • PARI's activity is essential for preserving genome stability, particularly in the context of DNA replication.
  • PARI represents a potential therapeutic target for mitigating genomic instability in cancer.

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