Oxidative stress and persistent activation of DNA damage response (DDR) are causally involved in the development of cellular senescence, a phenomenon implicated in fundamental (patho)physiological processes such as aging, fetal development and tumorigenesis. Here, we report that adenine nucleotide translocase-2 (ANT2) is consistently down-regulated in all three major forms of cellular senescence: replicative, oncogene-induced and drug-induced, in both normal and cancerous human cells. We previously reported formation of novel NF1/Smad transcription repressor complexes in growth-arrested fibroblasts. Here we show that such complexes form in senescent cells. Mechanistically, binding of the NF1/Smad complexes to the NF1-dependent repressor elements in the ANT2 gene promoter repressed ANT2 expression. Etoposide-induced formation of these complexes and repression of ANT2 were relatively late events co-incident with production and secretion of, and dependent on, TGF-β. siRNA-mediated knock-down of ANT2 in proliferating cells resulted in increased levels of reactive oxygen species (ROS) and activation of the DDR. Knock-down of ANT2, together with etoposide treatment, further intensified ROS production and DNA damage signaling, leading to enhanced apoptosis. Together, our data show that TGF-β-mediated suppression of ANT2 through NF1/Smad4 complexes contributes to oxidative stress and DNA damage during induction of cellular senescence.

Cancer Research Institute Slovak Academy of Sciences Vlarska 7 833 91 Bratislava Slovak Republic

Department of Biochemistry and Biophysics Arrhenius Laboratories Stockholm University S 106 91 Stockholm Sweden

Department of Genome Integrity Institute of Molecular Genetics v v i Academy of Sciences of the Czech Republic Videnska 1083 14220 Prague Czech Republic

Department of Genome Integrity Institute of Molecular Genetics v v i Academy of Sciences of the Czech Republic Videnska 1083 14220 Prague Czech Republic; Danish Cancer Society Research Center Copenhagen Denmark

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