The role of the RO60 (TROVE2) autoantigen in modulating cell-cycle progression, apoptosis and chemo-resistance in cancer cells

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The RO60 (TROVE2) proteins are highly conserved RNA-binding proteins which were identified as autoantigenes in patients with rheumatic diseases. From bacteria to men, RO60s were suggested as key modulators of the cellular stress response and were shown to promote cell survival upon UV-irradiation. So far, this protective role was mainly attributed to their functions in regulating the sequestering and degradation of misfolded non-coding RNAs, in particular the ribosomal 5S and U2 RNAs. How the proposed role of RO60s in regulating RNA-surveillance correlates with their involvement in rheumatic diseases remains poorly understood. Moreover, it remains elusive whether and how RO60s modulate tumor cell functions.In preliminary studies we observed that RO60s antagonize the p53-dependent upregulation of CDKN1A (p21) and enhance the drug- as well as UV-resistance of tumor-derived or transformed cells. This regulatory role appears to be facilitated by RO60-directed control of ATR-CK1 (ATR: ataxia telangiectasia and Rad3-related protein; CK1: check point kinase 1) (ATR: ataxia telangiectasia and Rad3-related protein; CK1: check point kinase 1) signaling and presumably involves altered binding to non-coding Y-RNAs. In previous studies, we demonstrated that these non-coding RNAs from small RNP-like complexes with RO60s and other RNA-binding proteins like IGF2BPs [Köhn et al., RNA 2010]. Supporting the protective role of RO60s, we found that the knockdown of RO60s reduced cell viability and sensitized tumor-derived cells to drugs, in particular gemcitabine, a frequently used chemotherapeutic which induces DNA-damage and replication block. Based on our preliminary studies we hypothesize that RO60s are key modulators of the cellular response to DNA-damage and support drug-/chemo-resistance of tumor cells. With the projects proposed we aim at characterizing how RO60s modulate the DNA-damage induced stress-response of tumor cells. Moreover, we intend to evaluate whether the depletion of specific RO60 isoforms sensitizes cancer-derived cells to chemotherapeutics and how this is modulated by p53-status. We expect that our studies will provide novel insights into the role of RO60s in tumor cells and will allow evaluating this family of RNA-binding proteins as future candidate targets for cancer treatment.