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Novel Smad proteins localize to IR-induced double-strand breaks: interplay between TGFβ and ATM pathways

Minli Wang1, Janapriya Saha, Megumi Hada

  • 1USRA Division of Life Sciences, Houston, TX 77058, USA.

Nucleic Acids Research
|December 11, 2012
PubMed

Insights

Ionizing radiation (IR) causes DNA damage, activating pathways like ATM and TGFβ. Smad proteins (Smad2, Smad7) are involved in this DNA damage response, interacting with ATM and TGFβ signaling.

Area of Science:

  • Cellular biology
  • Radiation biology
  • Molecular signaling

Background:

  • Ionizing radiation (IR) induces cellular damage via DNA damage and reactive oxygen species.
  • This damage activates DNA damage response (DDR) and cytokine signaling pathways, including ATM and TGFβ/Smad.
  • Understanding the interplay between these pathways is crucial for comprehending cellular responses to radiation.

Purpose of the Study:

  • To investigate the roles of Smad proteins in the DNA damage response to ionizing radiation.
  • To explore the crosstalk between the transforming growth factor-beta (TGFβ) and ataxia telangiectasia mutated (ATM) pathways following radiation exposure.
  • To characterize the behavior of Smad proteins in response to different types of radiation.

Main Methods:

  • Utilized double-strand break (DSB) markers to study Smad protein localization and dynamics.
  • Observed co-localization of phospho-Smad2 (pSmad2) and Smad7 with DSB repair proteins in human fibroblasts and epithelial cells.
  • Examined the effect of ATM depletion/inactivation and TGFβ receptor 1 (TGFβR1) inhibition on Smad foci formation.

Main Results:

  • Co-localization of pSmad2 and Smad7 with DSB repair proteins (e.g., γH2AX) was observed after low and high linear energy transfer (LET) radiation.
  • High LET radiation induced pSmad2 and Smad7 foci tracks along particle trajectories.
  • pSmad2 foci formation was dependent on ATM, while Smad7 foci formation was dependent on TGFβR1 signaling.

Conclusions:

  • Smad2 and Smad7 are recruited to sites of DNA damage following ionizing radiation.
  • Smad2's recruitment to DSBs is ATM-dependent, whereas Smad7's recruitment is TGFβR1-dependent.
  • These findings highlight a crosstalk between ATM and TGFβ signaling in the cellular response to radiation-induced DNA damage.

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