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Detection and Visualization of DNA Damage-induced Protein Complexes in Suspension Cell Cultures Using the Proximity Ligation Assay
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Pan-cancer antagonistic inhibition pattern of ATM-driven G2/M checkpoint pathway vs other DNA repair pathways

Marianna A Zolotovskaia1, Alexander A Modestov2, Maria V Suntsova3

  • 1Laboratory for Translational Genomic Bioinformatics, Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region 141701, Russia; Omicsway Corp., Walnut, CA, 91789, USA.

DNA Repair
|January 19, 2023
PubMed

Insights

Most DNA repair pathways are upregulated in cancers, but G2/M checkpoints and p53 pathways are notably downregulated. This suggests their critical roles in cancer progression and therapeutic resistance.

Area of Science:

  • Molecular Biology
  • Cancer Genomics
  • Biochemistry

Background:

  • DNA repair mechanisms are crucial for maintaining genome integrity.
  • These pathways can also promote cancer cell survival following genotoxic therapies.
  • Understanding DNA repair pathway dysregulation is key to cancer treatment strategies.

Purpose of the Study:

  • To investigate the activation status of 38 DNA repair pathways across nine human cancer types.
  • To compare DNA repair pathway activity in tumor samples versus normal tissues.
  • To identify specific pathways that are consistently altered during cancer development.

Main Methods:

  • Analysis of RNA sequencing and proteomic profiles from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium databases.
  • Screening of pathway activation levels in over 500 normal and 5700 tumor samples.
  • Statistical analysis to compare pathway activities between cancer types and normal tissues.

Main Results:

  • A congruent trend of G2/M arrest checkpoint pathway inhibition was observed in all analyzed cancer types compared to normal samples.
  • p53-mediated pathways showed relatively low activity across most cancer types.
  • Most other DNA repair pathways were found to be upregulated in the majority of cancer types.
  • The G2/M checkpoint pathway's downregulation was linked to antagonistic regulation of CCNB, CDK1, and GADD45 genes.
  • Loss-of-function mutations in ATM, TP53, and CDKN1A, and transforming mutations in cyclin B complex genes were identified.

Conclusions:

  • The activation of most DNA repair pathways is important for cancer progression.
  • The downregulation of the G2/M checkpoint and p53-related pathways represents a significant exception.
  • These findings highlight potential therapeutic targets and biomarkers for cancer treatment.
Keywords:
G2/M arrest pathwayMolecular pathway analysisOncobox clinical investigationProteomic profilingRNA sequencingSystems biology

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