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

Citace poskytuje Crossref.org

Determination of ADP/ATP translocase isoform ratios in malignancy and cellular senescence

Selective elimination of senescent cells by mitochondrial targeting is regulated by ANT2

Induction, regulation and roles of neural adhesion molecule L1CAM in cellular senescence

IFNγ induces oxidative stress, DNA damage and tumor cell senescence via TGFβ/SMAD signaling-dependent induction of Nox4 and suppression of ANT2