Deficiency in the catalytic subunit of DNA-Dependent protein kinase causes down-regulation of ATM

Peng, Yuanlin, Woods, Rick G., Beamish, Heather, Ye, Ruiqiong, Lees-Miller, Susan P., Lavin, Martin F. and Bedford, Joel S. (2005) Deficiency in the catalytic subunit of DNA-Dependent protein kinase causes down-regulation of ATM. Cancer Research, 65 5: 1670-1677. doi:10.1158/0008-5472.CAN-04-3451


Author Peng, Yuanlin
Woods, Rick G.
Beamish, Heather
Ye, Ruiqiong
Lees-Miller, Susan P.
Lavin, Martin F.
Bedford, Joel S.
Title Deficiency in the catalytic subunit of DNA-Dependent protein kinase causes down-regulation of ATM
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
1538-7445
Publication date 2005-03-01
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-04-3451
Volume 65
Issue 5
Start page 1670
End page 1677
Total pages 8
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Collection year 2005
Language eng
Formatted abstract
Previous reports have suggested a connection between reduced levels of the catalytic subunit of DNA-dependent protein kinases (DNA-PKcs), a component of the nonhomologous DNA double-strand breaks end-joining system, and a reduction in ATM. We studied this possible connection in other DNA-PKcs-deficient cell types, and following knockdown of DNA-PKcs with small interfering RNA, Chinese hamster ovary V3 cells, lacking DNA-PKcs, had reduced levels of ATM and hSMG-1, but both were restored after transfection with PRKDC. Atm levels were also reduced in murine scid cells. Reduction of ATM in a human glioma cell line lacking DNA-PKcs was accompanied by defective signaling through downstream substrates, post-irradiation. A large reduction of DNA-PKcs was achieved in normal human fibroblasts after transfection with two DNA-PKcs small interfering RNA sequences. This was accompanied by a reduction in ATM. These data were confirmed using immunocytochemical detection of. the proteins. Within hours after transfection, a decline in PRKDC mRNA was seen, followed by a more gradual decline in DNA-PKcs protein beginning 1 day after transfection. No change in ATM mRNA was observed for 2 days post-transfection. Only after the DNA-PKcs reduction occurred was a reduction in ATM mRNA observed, beginning 2 days post-transfection. The amount of ATM began to decline, starting about 3 days post-treatment, then it declined to levels comparable to DNA-PKcs. Both proteins returned to normal levels at later times. These data illustrate a potentially important cross-regulation between the nonhomologous end-joining system for rejoining of DNA double-strand breaks and the ATM-dependent damage response network of pathways, both of which operate to maintain the integrity of the genome.
Keyword DNA-PKcs
ATM
DNA breaks
NHEJ
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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Created: Wed, 15 Aug 2007, 06:49:47 EST