Dysregulated G2 phase checkpoint recovery pathway reduces DNA repair efficiency and increases chromosomal instability in a wide range of tumours

Area of Science:

• Cellular Biology
• Cancer Research
• Genetics

Background:

• Defective DNA repair is a hallmark of cancer, often present even without specific gene mutations.
• Cell cycle checkpoints coordinate DNA repair following damage, but defects in components like ATM are infrequent.
• The AURKA-PLK1 pathway's role in exiting G2 cell cycle arrest after DNA damage is not fully understood.

Purpose of the Study:

• Investigate the AURKA-PLK1 cell cycle checkpoint recovery pathway.
• Determine if dysregulation of this pathway contributes to DNA repair defects and genomic instability.
• Identify novel therapeutic targets for cancers with defective DNA repair.

Main Methods:

• Studied the effects of PP6 and AURKA dysregulation on PLK1 activation and cell cycle arrest.
• Assessed the impact of B55α subunit depletion on ATM and ATR checkpoint arrests.
• Correlated pathway dysregulation with genomic instability and homologous recombination deficiency signatures in cancer types.

Main Results:

• Dysregulation of PP6 and AURKA led to elevated PLK1, promoting premature exit from ATM-dependent arrest.
• Depletion of B55α (a PLK1 regulator) overcame both ATM and ATR checkpoint arrests.
• Checkpoint recovery pathway dysregulation reduced DNA repair efficiency and increased genomic instability.

Conclusions:

• Identified the PP6-AURKA-PLK1-B55α pathway as a novel source of G2 DNA repair defects and chromosomal instability.
• Found a correlation between this pathway's dysregulation and defective homologous recombination and chromosomal instability in various cancers.
• This pathway represents a potential therapeutic target for cancers exhibiting defective DNA repair.