TGFβ1 Protects Cells from γ-IR by Enhancing the Activity of the NHEJ Repair Pathway

Abstract

Several groups have reported that TGFb1 regulates cellular responses to g-irradiation; however, the exact mechanism has not been fully elucidated. In the current study, the role of TGFb1 in cellular responses to g-irradiation was investigated in detail. The data indicate that TGFb1 pretreatment decreased the aftermath of ionizing radiation (IR)-induced DNA damage in a SMAD-dependent manner. To determine the underlying mechanism for these effects, the extent of IR-induced DNA repair activity in the presence or absence of TGFb1 was examined. Studies reveal that TGFb1 upregulated DNA ligase IV (Lig4), augmented IR-induced nuclear retention of the DNA ligase, and enhanced nonhomologous end-joining (NHEJ) repair activity. In addition, knockdown of Lig4 reduced the TGFb1-induced protection against IR. Overall, these data indicate that TGFb1 facilitates the NHEJ repair process upon g-irradiation and thereby enhances long-term survival.Implications: These findings provide new insight and a possible approach to controlling genotoxic stress by the TGFb signaling pathway. Mol Cancer Res; 13(2); 319-29. Ó2014 AACR.

Subjugation of TGFβ Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End-Joining

“…NHEJ and HRR, are affected by TGFβ signaling. TGFβ positively regulates ligase IV (15), which is a critical player in NHEJ. The NHEJ repair pathway, which involves direct rejoining of DSB ends, is a fast but error-prone process that is functional throughout the cell cycle.…”

“…repair, cycle arrest and cell kill in vivo or in vitro (13). This is in part because TGFβ signaling is necessary for ataxia telangiectasia mutated (ATM) kinase activity during DNA damage (14) and ligase IV (15); both are important components of classical non-homologous end joining (NHEJ) repair of DNA damage. TGFβ also regulates breast cancer early onset 1 (BRCA1) (16,17), which is a major component of homologous recombination repair (HRR).…”

Modulation of inflammation by low and high doses of ionizing radiation: Implications for benign and malign diseases

“…Additionally, the immune cells create an anti-inflammatory microenvironment. A key player in this scenario again is the cytokine TGF-β1, which enhances the activity of the nonhomologous endjoining (NHEJ) DNA repair pathway [27] in cancer cells. It thereby induces immune suppression by influencing immune cells' development, differentiation, tolerance induction and homeostasis [28].…”

GARP is a key molecule for mesenchymal stromal cell responses to TGF-β and fundamental to control mitochondrial ROS levels

“…Although we have not characterized the nature of the TGF‐β responses in GARP −/low and GARP ++ ASCs, TGF‐β has been shown to cause cellular redox imbalance by inducing mtROS via the mTOR pathways and depleting glutathione via the JNK and induced activating transcription factor 3 pathway, which can result in DNA damage. In contrast, TGF‐β has also been shown to protect against genomic instability by enhancing nonhomologous end‐joining repair, ATM activity, and the SMAD3/β2spectrin/Fanconi anemia DNA repair pathway …”