DNA damage response involves modulation of Ku70 and Rb functions by cyclin A1 in leukemia cells.
Cyclin A1 plays a critical role in hematopoietic malignancies, notably, acute myeloid leukemia. The molecular mechanisms of cyclin A1 action are incompletely understood. Here, we show that cyclin A1 functions are mediated by the retinoblastoma and the Ku70 pathway. High levels of cyclin A1 and the associated CDK2 kinase activity were associated with increasing levels of phosphorylated retinoblastoma in vivo. UV irradiation induced a switch of the CDK2 towards cyclin A1, with accordance to changes in CDK2 kinase activity. The C-terminus of cyclin A1 directly interacted with Ku70, and DNA binding activity of Ku70 was modulated by cyclin A1/CDK2 and phosphatase treatment. Cyclin A1-deficiency induced by shRNA increased apoptosis that is induced by DNA damage and death receptor ligands. Taken together, these analyses demonstrate that cyclin A1 exerts antiapoptotic functions by interacting with retinoblastoma and Ku proteins in leukemia cells.
Ji
Ping
P
Department of Medicine, Hematology and Oncology, University of Münster, Münster, Germany.
Bäumer
Nicole
N
Yin
Taijun
T
Diederichs
Sven
S
Zhang
Feng
F
Beger
Carmela
C
Welte
Karl
K
Fulda
Simone
S
Berdel
Wolfgang E
WE
Serve
Hubert
H
Müller-Tidow
Carsten
C
D034961:Antigens, Nuclear / Q000378:metabolism*; D017209:Apoptosis; D045744:Cell Line, Tumor; D019925:Cyclin A / Q000378:metabolism* / Q000528:radiation effects; D056750:Cyclin A1; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D000072200:Ku Autoantigen; D007938:Leukemia / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D014466:Ultraviolet Rays
D034961:Antigens, Nuclear; C503745:CCNA1 protein, human; D019925:Cyclin A; D056750:Cyclin A1; D004268:DNA-Binding Proteins; D016160:Retinoblastoma Protein; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen