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

Research output: Contribution to journalArticle

43 Scopus citations

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 repair pathway termed nonhomologous end-joining (NHEJ). There are major 2 types of NHEJ: (1) the classical pathway initiated by the Ku complex, and (2) the alternative pathway initiated by poly ADP-ribose polymerase 1 (PARP1). Recent reports suggest that classical NHEJ repair components repress translocations, whereas alternative NHEJ components were required for translocations. The rate-limiting step for initiation of alternative NHEJ is the displacement of the Ku complex by PARP1. Therefore, we asked whether PARP1 inhibition could prevent chromosomal translocations in 3 translocation reporter systems. We found that 2 PARP1 inhibitors or repression of PARP1 protein expression strongly repressed chromosomal translocations, implying that PARP1 is essential for this process. Finally, PARP1 inhibition also reduced both ionizing radiation–generated and VP16-generated translocations in 2 cell lines. 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.

Original languageEnglish (US)
Pages (from-to)4359-4365
Number of pages7
JournalBlood
Volume121
Issue number21
DOIs
StatePublished - May 23 2013
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Wray, J., Williamson, E. A., Singh, S. B., Wu, Y., Cogle, C. R., Weinstock, D. M., Zhang, Y., Lee, S. H., Zhou, D., Shao, L., Hauer-Jensen, M., Pathak, R., Klimek, V., Nickoloff, J. A., & Hromas, R. (2013). PARP1 is required for chromosomal translocations. Blood, 121(21), 4359-4365. https://doi.org/10.1182/blood-2012-10-460527