Smad7 foci are present in micronuclei induced by heavy particle radiation

Minli Wang, Janapriya Saha, Francis A. Cucinotta

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

DNA damage and reactive oxygen species (ROS) generated by ionizing radiation (IR) activate DNA damage response (DDR) and cytokine signaling pathways, including double strand break (DSB) repair and TGFβ/Smad signaling pathway. Proteins assembled at IR-induced DSB sites can be visualized as foci, including γH2AX, 53BP1, ATM and ATF2. Unrepaired DSBs are thought to be one origin of micronuclei (MN), an indicator of genotoxic stress and chromosomal instability. Studies have detected γH2AX in IR-induced MN, indicating the presence of DSB in MN. Previously we reported that TGFβ downstream proteins Smad7 and phospho-Smad2 (pSmad2) co-localized with DDR proteins following radiation. Here we studied the status of Smad7 and pSmad2 in MN post high linear energy transfer (LET) radiation in human normal and cancerous cells. We observed γH2AX foci in IR-induced MN, whereas 53BP1 and ATF2 were absent. Interestingly, Smad7 foci, but not pSmad2, were detectable in both spontaneous and IR-induced MN. We compared the effect of particle track structures on the yield of MN using 5.6. MeV/u boron (B) and 600. MeV/u iron (Fe) particles with similar LET (200 and 180. keV/μm, respectively) in human fibroblasts. The frequency of MN induced by B was lower than that by Fe particles, albeit the proportion of Smad7-positive to Smad7-negative MN remained constant. An increased frequency of spontaneous MN, with slightly higher ratio of Smad7 or γH2AX positive, was found in human prostate cancer cells (PC3) compared to normal cells. 24. h after 1. Gy of Fe particles exposure, the yield of MN increased, and the majority (~70%) carried γH2AX and Smad7. Phospho-ATM (Ser1981) foci were found in both spontaneous and IR-induced MN in PC3 cells, displaying a much lower frequency compared to γH2AX and Smad7. Our data suggest a unique role of Smad7 in IR-induced MN formation, which may associate with DNA repair, apoptosis and genomic instability.

Original languageEnglish (US)
Pages (from-to)108-114
Number of pages7
JournalMutation Research - Genetic Toxicology and Environmental Mutagenesis
Volume756
Issue number1-2
DOIs
StatePublished - May 30 2013

Keywords

  • DNA repair
  • High LET radiation
  • Micronuclei
  • Smad7
  • TGFβ/Smad pathway

ASJC Scopus subject areas

  • Genetics
  • Health, Toxicology and Mutagenesis

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