Bcl2 negatively regulates DNA double-strand-break repair through a nonhomologous end-joining pathway.
Bcl2 can enhance susceptibility to carcinogenesis, but the mechanism(s) remains fragmentary. Here we discovered that Bcl2 suppresses DNA double-strand-break (DSB) repair and V(D)J recombination by downregulating Ku DNA binding activity, which is associated with increased genetic instability. Exposure of cells to ionizing radiation enhances Bcl2 expression in the nucleus, which interacts with both Ku70 and Ku86 via its BH1 and BH4 domains. Removal of the BH1 or BH4 domain abrogates the inhibitory effect of Bcl2 on Ku DNA binding, DNA-PK, and DNA end-joining activities, which results in the failure of Bcl2 to block DSB repair as well as V(D)J recombination. Intriguingly, Bcl2 directly disrupts the Ku/DNA-PKcs complex in vivo and in vitro. Thus, Bcl2 suppression of the general DSB repair and V(D)J recombination may occur in a mechanism by inhibiting the nonhomologous end-joining pathway, which may lead to an accumulation of DNA damage and genetic instability.
Wang
Qinhong
Q
UF Shands Cancer Center, University of Florida, Gainesville, FL 32610-3633, USA.
Gao
Fengqin
F
May
W Stratford
WS
Zhang
Yangde
Y
Flagg
Tammy
T
Deng
Xingming
X
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D000072200:Ku Autoantigen; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D011995:Recombination, Genetic; D015398:Signal Transduction / Q000502:physiology; D013347:Subcellular Fractions / Q000378:metabolism
D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D004265:DNA Helicases; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen