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Participation of ATM, SMG1, and DDX5 in a DNA Damage-Induced Alternative Splicing Pathway

Jennifer J McCann1, Donald E Fleenor1, Jing Chen1

  • 1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina 27710.

Radiation Research
|March 15, 2023
PubMed

Insights

DNA damage triggers a splicing pathway involving ATM, SMG1, and DDX5 kinases, regulating TP53 splicing and cellular senescence. This pathway is crucial for DNA repair and cancer progression.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Altered cellular responses to DNA damage are implicated in cancer development and therapeutic resistance.
  • The TP53 gene is frequently mutated in many cancer types.
  • DNA damage can induce alternative splicing pathways that modulate cellular stress responses.

Purpose of the Study:

  • To investigate the role of ATM, SMG1, and DDX5 in DNA damage-induced TP53 alternative splicing.
  • To confirm and extend previous findings on the regulation of TP53 splicing by DNA damage.
  • To elucidate the contribution of this pathway to radiation-induced cellular senescence.

Main Methods:

  • Ionizing radiation exposure to induce DNA damage.
  • Analysis of TP53 pre-mRNA alternative splicing.
  • Protein kinase activity assays (ATM, SMG1).
  • RNA immunoprecipitation (RIP) to study protein-RNA interactions (DDX5-SMG1).
  • Cellular senescence assays.

Main Results:

  • ATM protein kinase is required for SMG1 kinase activity repression after ionizing radiation.
  • The RNA helicase DDX5 interacts with SMG1 and is essential for TP53 pre-mRNA splicing to TP53b and TP53c variants.
  • DDX5 contributes to radiation-induced cellular senescence.
  • SMG1's role in alternative splicing is distinct from its role in nonsense-mediated RNA decay.

Conclusions:

  • ATM, SMG1, and DDX5 are key components of a DNA damage-induced alternative splicing pathway.
  • This pathway regulates TP53 splicing and influences radiation-induced cellular senescence.
  • Understanding this pathway offers insights into cancer progression and therapeutic resistance mechanisms.

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