Inhibition of nucleolar transcription by oxaliplatin involves ATM/ATR kinase signaling.

Platinum (Pt) compounds are an important class of anti-cancer therapeutics, but outstanding questions remain regarding their mechanism of action. Here, we demonstrate that oxaliplatin, a Pt drug used to treat colorectal cancer, inhibits rRNA transcription through ATM and ATR signaling, and induces DNA damage and nucleolar disruption. We show that oxaliplatin causes nucleolar accumulation of the nucleolar DNA damage response proteins (n-DDR) NBS1 and TOPBP1; however transcriptional inhibition does not depend upon NBS1 or TOPBP1, nor does oxaliplatin induce substantial amounts of nucleolar DNA damage, distinguishing the nucleolar response from previously characterized n-DDR pathways. Taken together, our work indicates that oxaliplatin induces a distinct ATM and ATR signaling pathway that functions to inhibit Pol I transcription in the absence of direct nucleolar DNA damage, demonstrating how nucleolar stress and transcriptional silencing can be linked to DNA damage signaling and highlighting an important mechanism of Pt drug cytotoxicity.

Oxaliplatin Inhibits RNA Polymerase I via DNA Damage Signaling Targeted to the Nucleolus.

Platinum (Pt) compounds are an important class of anti-cancer therapeutics, but outstanding questions remain regarding their mode of action. In particular, emerging evidence indicates that oxaliplatin, a Pt drug used to treat colorectal cancer, kills cells by inducing ribosome biogenesis stress rather than through DNA damage generation, but the underlying mechanism is unknown. Here, we demonstrate that oxaliplatin-induced ribosomal RNA (rRNA) transcriptional silencing and nucleolar stress occur downstream of DNA damage signaling involving ATM and ATR. We show that NBS1 and TOPBP1, two proteins involved in the nucleolar DNA damage response (n-DDR), are recruited to nucleoli upon oxaliplatin treatment. However, we find that rRNA transcriptional inhibition by oxaliplatin does not depend upon NBS1 or TOPBP1, nor does oxaliplatin induce substantial amounts of nucleolar DNA damage, distinguishing it from previously characterized n-DDR pathways. Taken together, our work indicates that oxaliplatin induces a distinct DDR signaling pathway that functions in trans to inhibit Pol I transcription in the nucleolus, demonstrating how nucleolar stress can be linked to DNA damage signaling and highlighting an important mechanism of Pt drug cytotoxicity.