BCR-ABL promotes the frequency of mutagenic single-strand annealing DNA repair.
Intracellular oxidative stress in cells transformed by the BCR-ABL oncogene is associated with increased DNA double-strand breaks. Imprecise repair of these breaks can result in the accumulation of mutations, leading to therapy-related drug resistance and disease progression. Using several BCR-ABL model systems, we found that BCR-ABL specifically promotes the repair of double-strand breaks through single-strand annealing (SSA), a mutagenic pathway that involves sequence repeats. Moreover, our results suggest that mutagenic SSA repair can be regulated through the interplay between BCR-ABL and extrinsic growth factors. Increased SSA activity required Y177 in BCR-ABL, as well as a functional PI3K and Ras pathway downstream of this site. Furthermore, our data hint at a common pathway for DSB repair whereby BCR-ABL, Tel-ABL, Tel-PDGFR, FLT3-ITD, and Jak2V617F all increase mutagenic repair. This increase in SSA may not be sufficiently suppressed by tyrosine kinase inhibitors in the stromal microenvironment. Therefore, drugs that target growth factor receptor signaling represent potential therapeutic agents to combat tyrosine kinase-induced genomic instability.
Fernandes
Margret S
MS
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Reddy
Mamatha M
MM
Gonneville
Jeffrey R
JR
DeRoo
Scott C
SC
Podar
Klaus
K
Griffin
James D
JD
Weinstock
David M
DM
Sattler
Martin
M
D000818:Animals; D001483:Base Sequence; D004260:DNA Repair; D004277:DNA, Single-Stranded / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology; D018631:ras Proteins / Q000378:metabolism
D004277:DNA, Single-Stranded; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; D018631:ras Proteins