Bora downregulation results in radioresistance by promoting repair of double strand breaks.
Following DNA double-strand breaks cells activate several DNA-damage response protein kinases, which then trigger histone H2AX phosphorylation and the accumulation of proteins such as MDC1, p53-binding protein 1, and breast cancer gene 1 at the damage site to promote DNA double-strand breaks repair. We identified a novel biomarker, Bora (previously called C13orf34), that is associated with radiosensitivity. In the current study, we set out to investigate how Bora might be involved in response to irradiation. We found a novel function of Bora in DNA damage repair response. Bora down-regulation increased colony formation in cells exposed to irradiation. This increased resistance to irradiation in Bora-deficient cells is likely due to a faster rate of double-strand breaks repair. After irradiation, Bora-knockdown cells displayed increased G2-M cell cycle arrest and increased Chk2 phosphorylation. Furthermore, Bora specifically interacted with the tandem breast cancer gene 1 C-terminal domain of MDC1 in a phosphorylation dependent manner, and overexpression of Bora could abolish irradiation induced MDC1 foci formation. In summary, Bora may play a significant role in radiosensitivity through the regulation of MDC1 and DNA repair.
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, 55905, United States of America.
Junmei
J
Cairns
Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, 44106, United States of America.
Yi
Y
Peng
Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, 44106, United States of America.
Vivien C
VC
Yee
Department of Oncology and Oncology Research, Mayo Clinic, Rochester, Minnesota, 55905, United States of America.
Zhenkun
Z
Lou
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, 55905, United States of America.
Liewei
L
Wang
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000528:radiation effects; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011836:Radiation Tolerance; D015534:Trans-Activators / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D047908:Intracellular Signaling Peptides and Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; C498301:TP53BP1 protein, human; D015534:Trans-Activators; D000071857:Tumor Suppressor p53-Binding Protein 1; C528235:bora protein, human