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

Wang, Minli; Saha, Janapriya; Hada, Megumi; Anderson, Jennifer A.; Pluth, Janice M.; O’Neill, Peter; Cucinotta, Francis A.

doi:10.1093/nar/gks1038

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

Journal Article · Wed Dec 05 00:00:00 EST 2012 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gks1038· OSTI ID:1625498

Wang, Minli ^[1]; Saha, Janapriya ^[2]; Hada, Megumi ^[2]; Anderson, Jennifer A. ^[3]; Pluth, Janice M. ^[4]; O’Neill, Peter ^[3]; Cucinotta, Francis A. ^[5]

Universities Space Research Association (USRA), Houston, TX (United States). Division of Life Sciences; DOE/OSTI
Universities Space Research Association (USRA), Houston, TX (United States). Division of Life Sciences
Univ. of Oxford (United Kingdom). Gray Inst. for Radiation Oncology and Biology
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
NASA Johnson Space Center, Houston, TX (United States). Space Radition Program

Cellular damage from ionizing radiation (IR) is in part due to DNA damage and reactive oxygen species, which activate DNA damage response (DDR) and cytokine signaling pathways, including the ataxia telangiectasia mutated (ATM) and transforming growth factor (TGF)b/Smad pathways. Using classic double-strand breaks (DSBs) markers, we studied the roles of Smad proteins in DDR and the crosstalk between TGFb and ATM pathways. We observed co-localization of phospho-Smad2 (pSmad2) and Smad7 with DSB repair proteins following low and high linear energy transfer (LET) radiation in human fibroblasts and epithelial cells. The decays of both foci were similar to that of cH2AX foci. Irradiation with high LET particles induced pSmad2 and Smad7 foci tracks indicating the particle trajectory through cells. pSmad2 foci were absent in S phase cells, while Smad7 foci were present in all phases of cell cycle. pSmad2 (but not Smad7) foci were completely abolished when ATM was depleted or inactivated. In contrast, a TGFb receptor 1 (TGFbR1) inhibitor abrogated Smad7, but not pSmad2 foci at DSBs sites. In summary, we suggest that Smad2 and Smad7 contribute to IR-induced DSB signaling in an ATM or TGFbR1-dependent manner, respectively.

View Accepted Manuscript (DOE)

Research Organization:: NASA Johnson Space Center, Houston, TX (United States); Univ. of Oxford (United Kingdom)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: SC0002296; SC0002453

OSTI ID:: 1625498

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 2 Vol. 41; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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