p210 BCR/ABL kinase regulates nucleotide excision repair (NER) and resistance to UV radiation.
Both clinical and experimental evidence illustrate that p190 and p210 BCR/ABL oncogenic tyrosine kinases induce resistance to DNA damage and confer an intrinsic genetic instability. Here, we investigated whether BCR/ABL expression could modulate nucleotide excision repair (NER). We found that ectopic expression of p210 BCR/ABL in murine lymphoid BaF3 cell line inhibited NER activity in vitro, promoting hypersensitivity of these cells to ultraviolet (UV) treatment and facilitating a mutator phenotype. However, expression of p210 BCR/ABL in human and murine myeloid cell lines and primary bone marrow cells resulted in the increased NER activity and resistance to UV irradiation. The ABL tyrosine kinase inhibitor STI571 reversed these effects, showing that p210 BCR/ABL tyrosine kinase activity is responsible for deregulation of NER. Hypoactivity of NER in p210 BCR/ABL-positive lymphoid cells was accompanied by the decreased interaction between proliferating cell nuclear antigen (PCNA) and xeroderma pigmentosum group B (XPB); conversely, this interaction was enhanced in p210 BCR/ABL-positive myeloid cells. p190 BCR/ABL did not affect NER in lymphoid and myeloid cells. In summary, our study suggests that p210 BCR/ABL reduced NER activity in lymphoid cells, leading to hypersensitivity to UV and mutagenesis. In contrast, p210 BCR/ABL expression in myeloid cells facilitated NER and induced resistance to UV.
Canitrot
Yvan
Y
Genetic Instability and Cancer, Institut de Pharmacologie et Biologie Structurale, Toulouse, France.
Falinski
Rafal
R
Louat
Thierry
T
Laurent
Guy
G
Cazaux
Christophe
C
Hoffmann
Jean-Sébastien
JS
Lautier
Dominique
D
Skorski
Tomasz
T
D000818:Animals; D002470:Cell Survival / Q000502:physiology / Q000528:radiation effects; D004265:DNA Helicases; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl; D051379:Mice; D016296:Mutagenesis / Q000528:radiation effects; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011836:Radiation Tolerance / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000201:enzymology / Q000528:radiation effects; D014466:Ultraviolet Rays
D004268:DNA-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; C072022:XPBC-ERCC-3 protein; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D004265:DNA Helicases