RNA polymerase II is Hyperphosphorylated in Response to Topoisomerase I-DNA Cleavage Complexes and is Associated with Transcription- and BRCA1-Dependent Degradation of Topoisomerase I

The progression of RNA polymerase II can be blocked by lesions on the DNA template. In this study, we focused in the modifications of the largest subunit of RNA polymerase II, Rpb1, in response to stabilized topoisomerase I (Top1)-DNA cleavage complexes. In addition to DNA modifications (base damage...

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Veröffentlicht in:Journal of molecular biology 2008-06, Vol.381 (3), p.540-549
Hauptverfasser: Sordet, Olivier, Larochelle, Stéphane, Nicolas, Estelle, Stevens, Ellen V., Zhang, Chao, Shokat, Kevan M., Fisher, Robert P., Pommier, Yves
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Sprache:eng
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Zusammenfassung:The progression of RNA polymerase II can be blocked by lesions on the DNA template. In this study, we focused in the modifications of the largest subunit of RNA polymerase II, Rpb1, in response to stabilized topoisomerase I (Top1)-DNA cleavage complexes. In addition to DNA modifications (base damages and strand breaks), Top1 cleavage complexes can be trapped by camptothecin and its derivatives used in cancer treatment. We find that, within a few minutes, camptothecin produces the complete hyperphosphorylation of Rpb1 in both primary and transformed cancer cells. Hyperphosphorylation is rapidly reversible following camptothecin removal. Hyperphosphorylation occurs selectively on the serine-5 residue of the conserved heptapeptide repeats in the Rpb1-carboxy-terminal domain and is mediated principally by the TFIIH-associated kinase, Cdk7. Hyperphosphorylated Rpb1 is not primarily targeted for proteosomal degradation, but instead is subjected to cycles of phosphorylation and dephosphorylation as long as Top1 cleavage complexes are trapped by camptothecin. Finally, we show that transcription-induced degradation of Top1 is Brca1-dependent, suggesting a role for Brca1 in the repair or removal of transcription-blocking Top1-DNA cleavage complexes.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2008.06.028