title: c-ABL tyrosine kinase stabilizes RAD51 chromatin association.
abstract: The assembly of RAD51 recombinase on DNA substrates at sites of breakage is essential for their repair by homologous recombination repair (HRR). The signaling pathway that triggers RAD51 assembly at damage sites to form subnuclear foci is unclear. Here, we provide evidence that c-ABL, a tyrosine kinase activated by DNA damage which phosphorylates RAD51 on Tyr-315, works at a previously unrecognized, proximal step to initiate RAD51 assembly. We first show that c-ABL associates with chromatin after DNA damage in a manner dependent on its kinase activity. Using RAD51 mutants that are unable to oligomerize to form a nucleoprotein filament, we separate RAD51 assembly on DNA to form foci into two steps: stable chromatin association followed by oligomerization. We show that phosphorylation on Tyr-315 by c-ABL is required for chromatin association of oligomerization-defective RAD51 mutants, but is insufficient to restore oligomerization. Our findings suggest a new model for the regulation of early steps of HRR.
authors.affiliation: Department of Molecular Pathology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimizu
authors.forename: Milena
authors.initials: M
authors.lastname: Popova
authors.forename: Fabrice
authors.initials: F
authors.lastname: Fleury
authors.forename: Masahiko
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hayashi
authors.forename: Isao
authors.initials: I
authors.lastname: Sakane
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kurumizaka
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Venkitaraman
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D010766:Phosphorylation; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D014443:Tyrosine; D016315:Proto-Oncogene Proteins c-abl; D051135:Rad51 Recombinase