Ultraviolet irradiation induces BRCA2 protein depletion through a p53-independent and protein synthesis-dependent pathway.
It has been suggested that BRCA2, the protein product of the breast cancer susceptibility gene BRCA2, is involved in DNA damage repair. It is therefore likely that BRCA2 plays a role in a signaling pathway induced by DNA-damaging agents. To test this possibility, we examined the alteration of the BRCA2 protein level in human cell lines after UV irradiation. We found that UV irradiation down-regulated BRCA2 in a dose-dependent manner in all cell lines tested. The down-regulation of BRCA2 occurred soon (within 4 h) after UV treatment. Surprisingly, down-regulation of BRCA2 by UV does not require functional p53, which has been suggested to be required for the down-regulation of BRCA1 and BRCA2 mRNAs by DNA-damaging agents. Moreover, the proteosome- and calpain-mediated protein degradation pathways do not have an important role in the UV-induced BRCA2 depletion. However, blocking protein synthesis temporally inhibited the depletion of BRCA2 and BRCA1 in some cell lines. Ectopic expression of BRCA2 in cells increased resistance of cells to high-dose UV irradiation. These results demonstrate that BRCA2 is involved in a DNA-damaging signaling pathway induced by UV radiation and that expression of BRCA2 can protect cells from UV-mediated cell death.
Wang
S C
SC
Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Makino
K
K
Su
L K
LK
Pao
A Y
AY
Kim
J S
JS
Hung
M C
MC
D019313:BRCA1 Protein / Q000096:biosynthesis; D024682:BRCA2 Protein; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation / Q000528:radiation effects; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000378:metabolism / Q000528:radiation effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism / Q000528:radiation effects*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014466:Ultraviolet Rays
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D009363:Neoplasm Proteins; D011500:Protein Synthesis Inhibitors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D003513:Cycloheximide