Ran Binding Protein 9 (RanBP9) is a novel mediator of cellular DNA damage response in lung cancer cells
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Dario Palmieri1,2, Mario Scarpa1,2, Anna Tessari1, Rexhep Uka1,2, Foued Amari1,2, Cindy Lee1,2, Timothy Richmond1, Claudia Foray1,2 Tyler Sheetz1, Ashley Braddom1, Christin E. Burd1,2, Jeffrey D. Parvin1,2, Thomas Ludwig1,2, Carlo M. Croce1, Vincenzo Coppola1,2
1Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, 43210 Columbus, OH, USA
2Solid Tumor Biology Program, Comprehensive Cancer Center, The Ohio State University, 43210 Columbus, OH, USA
Vincenzo Coppola, e-mail: Vincenzo.firstname.lastname@example.org
Keywords: RanBP9, RanBPM, ATM, DNA damage, ionizing radiation
Received: December 09, 2015 Accepted: January 29, 2016 Published: March 01, 2016
Ran Binding Protein 9 (RanBP9, also known as RanBPM) is an evolutionary conserved scaffold protein present both in the nucleus and the cytoplasm of cells whose biological functions remain elusive.
We show that active ATM phosphorylates RanBP9 on at least two different residues (S181 and S603). In response to IR, RanBP9 rapidly accumulates into the nucleus of lung cancer cells, but this nuclear accumulation is prevented by ATM inhibition. RanBP9 stable silencing in three different lung cancer cell lines significantly affects the DNA Damage Response (DDR), resulting in delayed activation of key components of the cellular response to IR such as ATM itself, Chk2, γH2AX, and p53. Accordingly, abrogation of RanBP9 expression reduces homologous recombination-dependent DNA repair efficiency, causing an abnormal activation of IR-induced senescence and apoptosis.
In summary, here we report that RanBP9 is a novel mediator of the cellular DDR, whose accumulation into the nucleus upon IR is dependent on ATM kinase activity. RanBP9 absence hampers the molecular mechanisms leading to efficient repair of damaged DNA, resulting in enhanced sensitivity to genotoxic stress. These findings suggest that targeting RanBP9 might enhance lung cancer cell sensitivity to genotoxic anti-neoplastic treatment.
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