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MBC in Press, published online ahead of print July 16, 2008
Mol. Biol. Cell 10.1091/mbc.E08-02-0215

A more recent version of this article appeared on September 1, 2008
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Submitted on February 28, 2008
Revised on June 20, 2008
Accepted on June 29, 2008

Transcription-coupled DNA Double-Strand Breaks Are Mediated via the Nucleotide Excision Repair and the Mre11-Rad50-Nbs1 Complex

Josée Guirouilh-Barbat, Christophe Redon, and Yves Pommier

Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255

Monitoring Editor: John L. Cleveland

The cellular activity of Yondelis® (Trabectedin, Ecteinascidin 743, Et743) is known to depend on transcription-coupled-nucleotide excision repair (TCR). However, the subsequent cellular effects of Et743 are not fully understood. Here we show that Et743 induces both transcription- and replication-coupled DNA double-strand breaks (DSBs) that are detectible by neutral COMET assay and as {gamma}-H2AX foci that colocalize with 53BP1, Mre11, Ser1981-pATM, and Thr68-pChk2. The transcription coupled-DSBs (TC-DSBs) induced by Et743 depended both on TCR and Mre11-Rad50-Nbs1 (MRN) and were associated with DNA-PK-dependent {gamma}-H2AX foci. In contrast to DNA-PK, ATM phosphorylated H2AX both in NER-proficient and –deficient cells, but its full activation was dependent on H2AX as well as DNA-PK, suggesting a positive feedback loop: DNA-PK-{gamma}-H2AX-ATM. Knocking-out H2AX or inactivating DNA-PK reduced Et743’s antiproliferative activity while ATM and MRN tended to act as survival factors. Our results highlight the interplays between ATM and DNA-PK, and their impacts on H2AX phosphorylation and cell survival. They also suggest that {gamma}-H2AX may serve as a biomarker in patients treated with Et743 and that molecular profiling of tumors for TCR, MRN, ATM, and DNA-PK might be useful to anticipate tumor response to Et743 treatment.

Address correspondence to: Yves Pommier (pommier{at}nih.gov)




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