Blood Journal
Leading the way in experimental and clinical research in hematology

PARP1 is required for chromosomal translocations

  1. Justin Wray1,
  2. Elizabeth A. Williamson1,
  3. Sudha B. Singh1,
  4. Yuehan Wu1,
  5. Christopher R. Cogle1,
  6. David M. Weinstock2,
  7. Yu Zhang3,
  8. Suk-Hee Lee4,
  9. Daohong Zhou5,
  10. Lijian Shao5,
  11. Martin Hauer-Jensen5,
  12. Rupak Pathak5,
  13. Virginia Klimek6,
  14. Jac A. Nickoloff7, and
  15. Robert Hromas1,*
  1. 1 Department of Medicine, University of Florida College of Medicine, Gainesville, FL, United States;
  2. 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States;
  3. 3 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, United States;
  4. 4 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States;
  5. 5 Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States;
  6. 6 Department of Hematology, Memorial Sloan Kettering Cancer Center, New York, NY, United States;
  7. 7 Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO, United States
  1. * Corresponding author; email: robert.hromas{at}

Key points

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


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.