title: c-Abl downregulates the slow phase of double-strand break repair.
abstract: c-Abl tyrosine kinase is activated by agents that induce double-strand DNA breaks (DSBs) and interacts with key components of the DNA damage response and of the DSB repair machinery. However, the functional significance of c-Abl in these processes, remained unclear. In this study, we demonstrate, using comet assay and pulsed-field gel electrophoresis, that c-Abl inhibited the repair of DSBs induced by ionizing radiation, particularly during the second and slow phase of DSB repair. Pharmacological inhibition of c-Abl and c-Abl depletion by siRNA-mediated knockdown resulted in higher DSB rejoining. c-Abl null MEFs exhibited higher DSB rejoining compared with cells reconstituted for c-Abl expression. Abrogation of c-Abl kinase activation resulted in higher H2AX phosphorylation levels and higher numbers of post-irradiation γH2AX foci, consistent with a role of c-Abl in DSB repair regulation. In conjunction with these findings, transient abrogation of c-Abl activity resulted in increased cellular radioresistance. Our findings suggest a novel function for c-Abl in inhibition of the slow phase of DSB repair.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: V
authors.initials: V
authors.lastname: Meltser
authors.forename: M
authors.initials: M
authors.lastname: Ben-Yehoyada
authors.forename: N
authors.initials: N
authors.lastname: Reuven
authors.forename: Y
authors.initials: Y
authors.lastname: Shaul
mesh_terms: D000818:Animals; D020552:Comet Assay; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D015536:Down-Regulation; D016521:Electrophoresis, Gel, Pulsed-Field; D006657:Histones / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D006657:Histones; D034741:RNA, Small Interfering; D016315:Proto-Oncogene Proteins c-abl