title: PARP1 is required for chromosomal translocations.
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.
authors.affiliation: Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Wray
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Williamson
authors.forename: Sudha B
authors.initials: SB
authors.lastname: Singh
authors.forename: Yuehan
authors.initials: Y
authors.lastname: Wu
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Cogle
authors.forename: David M
authors.initials: DM
authors.lastname: Weinstock
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Suk-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.forename: Lijian
authors.initials: L
authors.lastname: Shao
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
authors.forename: Rupak
authors.initials: R
authors.lastname: Pathak
authors.forename: Virginia
authors.initials: V
authors.lastname: Klimek
authors.forename: Jac A
authors.initials: JA
authors.lastname: Nickoloff
authors.forename: Robert
authors.initials: R
authors.lastname: Hromas
mesh_terms: D000208:Acute Disease; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000517:prevention & control; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D014178:Translocation, Genetic / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*
chemical_list: D007211:Indoles; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; C531549:rucaparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib