Year: 2013
Type: article
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.
Source: Blood
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: G1836831008, G2053876048, Cancer Therapy-induced Long-term Bone Marrow Injury, G3284541283, G3380100404, G5210355207, G6148868134, G8626897305, Metnase, PIKK, and RPA Roles in DNA Damage and Replication Stress Responses, TRANSPOSASE PROTEIN METNASE IN LEUKEMIC DECATENATION, G9000055765, G9000341311, G939687621
OpenAlex ID: W1989714107