PARP1 is required for chromosomal translocations
| Autor: | Sudha B. Singh, Rupak Pathak, Daohong Zhou, Lijian Shao, Yuehan Wu, David M. Weinstock, Elizabeth A. Williamson, Jac A. Nickoloff, Martin Hauer-Jensen, Suk Hee Lee, Virginia M. Klimek, Christopher R. Cogle, Yu Zhang, Robert Hromas, Justin Wray |
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| Rok vydání: | 2013 |
| Předmět: |
Indoles
Poly ADP ribose polymerase Immunology Poly (ADP-Ribose) Polymerase-1 Chromosomal translocation Poly(ADP-ribose) Polymerase Inhibitors Biochemistry Poly (ADP-Ribose) Polymerase Inhibitor Piperazines Translocation Genetic Classical complement pathway PARP1 Humans DNA Breaks Double-Stranded RNA Small Interfering Psychological repression Cells Cultured Polymerase Myeloid Neoplasia Leukemia biology fungi food and beverages Cell Biology Hematology Fibroblasts Acute Disease Alternative complement pathway biology.protein Cancer research Phthalazines Poly(ADP-ribose) Polymerases |
| Zdroj: | Blood. 121:4359-4365 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2012-10-460527 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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