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PARP1 is required for chromosomal translocations

Justin Wray, Elizabeth A. Williamson, Sudha B. Singh, Yuehan Wu, Christopher R. Cogle, David M. Weinstock, Yu Zhang, Suk-Hee Lee, Daohong Zhou, Lijian Shao, Martin Hauer-Jensen, Rupak Pathak, Virginia Klimek, Jac A. Nickoloff, Robert Hromas

Key points

  • Chromosomal translocations are mediated by PARP1, and can be suppressed by the clinical PARP1 inhibitors

Abstract

Chromosomal translocations are common contributors to malignancy, yet little is known about the precise molecular mechanisms by which they are generated. Sequencing translocation junctions in acute leukemias revealed that the translocations were likely mediated by a DNA double-strand break (DSB) repair pathway termed non-homologous end joining (NHEJ). There are major two types of NHEJ, the more common classical pathway initiated by the Ku complex, and the alternative pathway initiated by PARP1. Recent reports suggest that classical non-homologous end joining (cNHEJ) repair components repress translocations, rather than promote them. Conversely, the alternative NHEJ (aNHEJ) components DNA Ligase III and CtIP were found to be required for translocations. The rate limiting step for initiation of aNHEJ is the displacement of the Ku complex by PARP1. We therefore asked whether small molecule PARP1 inhibitors could prevent chromosomal translocations in three translocation reporter systems. We found that the PARP1 inhibitors olaparib and rucaparib at clinically achievable concentrations strongly repressed chromosomal translocations, implying that PARP1 is essential for this process. In addition, when PARP1 protein was repressed with siRNA translocation efficiencies were almost completely abrogated. Finally, olaparib also reduced ionizing radiation-generated translocations in normal human fibroblast cells and VP16-generated translocations in a murine hematopoietic progenitor line. These data define PARP1 as a critical mediator of chromosomal translocations, and raise the possibility that oncogenic translocations occurring after high dose chemotherapy or radiation could be prevented by treatment with a clinically available PARP1 inhibitor.

  • Submitted October 9, 2012.
  • Accepted March 23, 2013.