title: Targeting RAD51 phosphotyrosine-315 to prevent unfaithful recombination repair in BCR-ABL1 leukemia.
abstract: Chronic myeloid leukemia chronic phase (CML-CP) CD34(+) cells contain numerous DNA double-strand breaks whose unfaithful repair may contribute to chromosomal instability and disease progression to blast phase (CML-BP). These phenomena are often associated with the appearance of imatinib-resistant BCR-ABL1 kinase mutants (eg, T315I) and overexpression of BCR-ABL1. Here we show that BCR-ABL1 (nonmutated and T315I mutant) promoted RAD51 recombinase-mediated unfaithful homeologous recombination repair (HomeoRR) in a dosage-dependent manner. BCR-ABL1 SH3 domain interacts with RAD51 proline-rich regions, resulting in direct phosphorylation of RAD51 on Y315 (pY315). RAD51(pY315) facilitates dissociation from the complex with BCR-ABL1 kinase, migrates to the nucleus, and enhances formation of the nuclear foci indicative of recombination sites. HomeoRR and RAD51 nuclear foci were strongly reduced by RAD51(Y315F) phosphorylation-less mutant. In addition, peptide aptamer mimicking RAD51(pY315) fragment, but not that with Y315F phosphorylation-less substitution, diminished RAD51 foci formation and inhibited HomeoRR in leukemia cells. In conclusion, we postulate that BCR-ABL1 kinase-mediated RAD51(pY315) promotes unfaithful HomeoRR in leukemia cells, which may contribute to accumulation of secondary chromosomal aberrations responsible for CML relapse and progression.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA, USA.
authors.forename: Artur
authors.initials: A
authors.lastname: Slupianek
authors.forename: Yashodhara
authors.initials: Y
authors.lastname: Dasgupta
authors.forename: Shu-Yue
authors.initials: SY
authors.lastname: Ren
authors.forename: Ewa
authors.initials: E
authors.lastname: Gurdek
authors.forename: Milene
authors.initials: M
authors.lastname: Donlin
authors.forename: Margaret
authors.initials: M
authors.lastname: Nieborowska-Skorska
authors.forename: Fabrice
authors.initials: F
authors.lastname: Fleury
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004260:DNA Repair / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D051379:Mice; D016133:Polymerase Chain Reaction; D051135:Rad51 Recombinase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
chemical_list: D014443:Tyrosine; D016044:Fusion Proteins, bcr-abl; D051135:Rad51 Recombinase