The catalytic subunit of DNA-dependent protein kinase is downstream of ATM and feeds forward oxidative stress in the selenium-induced senescence response

Caroline R B Rocourt, Min Wu, Benjamin P C Chen, Wen Hsing Cheng

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Selenium induces a senescence response in cells through induction of ataxia-telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in DNA double-strand break repair is established, it is unclear how these proteins function in response to selenium-induced oxidative stress and senescence induction. In this study, we demonstrated that pretreating normal human diploid fibroblasts with DNA-PK kinase inhibitor NU 7026 suppressed selenium-induced senescence response. Selenium treatment induced phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which was decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidants N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 was not affected by NU 7026. Cells deficient in DNA-PKcs or pretreated with NU 7026 or N-acetylcysteine were defective in selenite-induced ROS formation. Taken together, these results indicate a distinct role of DNA-PKcs, in which this kinase can respond to and feed forward selenium-induced ROS formation and is placed downstream of ATM in the resultant senescence response.

Original languageEnglish (US)
Pages (from-to)781-787
Number of pages7
JournalJournal of Nutritional Biochemistry
Volume24
Issue number5
DOIs
StatePublished - May 2013

Fingerprint

DNA-Activated Protein Kinase
Catalytic DNA
Ataxia Telangiectasia
Oxidative stress
Selenium
Catalytic Domain
Oxidative Stress
DNA
Reactive Oxygen Species
Phosphorylation
Phosphotransferases
Acetylcysteine
Polynucleotide 5'-Hydroxyl-Kinase
Selenious Acid
Double-Stranded DNA Breaks
Fibroblasts
Diploidy
Repair
Antioxidants
2-(morpholin-4-yl)benzo(h)chromen-4-one

Keywords

  • ATM
  • DNA-PK
  • Selenium
  • Senescence

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Endocrinology, Diabetes and Metabolism
  • Nutrition and Dietetics

Cite this

The catalytic subunit of DNA-dependent protein kinase is downstream of ATM and feeds forward oxidative stress in the selenium-induced senescence response. / Rocourt, Caroline R B; Wu, Min; Chen, Benjamin P C; Cheng, Wen Hsing.

In: Journal of Nutritional Biochemistry, Vol. 24, No. 5, 05.2013, p. 781-787.

Research output: Contribution to journalArticle

@article{50665822c57d4d6d88511fc8e589f856,
title = "The catalytic subunit of DNA-dependent protein kinase is downstream of ATM and feeds forward oxidative stress in the selenium-induced senescence response",
abstract = "Selenium induces a senescence response in cells through induction of ataxia-telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in DNA double-strand break repair is established, it is unclear how these proteins function in response to selenium-induced oxidative stress and senescence induction. In this study, we demonstrated that pretreating normal human diploid fibroblasts with DNA-PK kinase inhibitor NU 7026 suppressed selenium-induced senescence response. Selenium treatment induced phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which was decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidants N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 was not affected by NU 7026. Cells deficient in DNA-PKcs or pretreated with NU 7026 or N-acetylcysteine were defective in selenite-induced ROS formation. Taken together, these results indicate a distinct role of DNA-PKcs, in which this kinase can respond to and feed forward selenium-induced ROS formation and is placed downstream of ATM in the resultant senescence response.",
keywords = "ATM, DNA-PK, Selenium, Senescence",
author = "Rocourt, {Caroline R B} and Min Wu and Chen, {Benjamin P C} and Cheng, {Wen Hsing}",
year = "2013",
month = "5",
doi = "10.1016/j.jnutbio.2012.04.011",
language = "English (US)",
volume = "24",
pages = "781--787",
journal = "Journal of Nutritional Biochemistry",
issn = "0955-2863",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - The catalytic subunit of DNA-dependent protein kinase is downstream of ATM and feeds forward oxidative stress in the selenium-induced senescence response

AU - Rocourt, Caroline R B

AU - Wu, Min

AU - Chen, Benjamin P C

AU - Cheng, Wen Hsing

PY - 2013/5

Y1 - 2013/5

N2 - Selenium induces a senescence response in cells through induction of ataxia-telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in DNA double-strand break repair is established, it is unclear how these proteins function in response to selenium-induced oxidative stress and senescence induction. In this study, we demonstrated that pretreating normal human diploid fibroblasts with DNA-PK kinase inhibitor NU 7026 suppressed selenium-induced senescence response. Selenium treatment induced phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which was decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidants N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 was not affected by NU 7026. Cells deficient in DNA-PKcs or pretreated with NU 7026 or N-acetylcysteine were defective in selenite-induced ROS formation. Taken together, these results indicate a distinct role of DNA-PKcs, in which this kinase can respond to and feed forward selenium-induced ROS formation and is placed downstream of ATM in the resultant senescence response.

AB - Selenium induces a senescence response in cells through induction of ataxia-telangiectasia mutated (ATM) and reactive oxygen species (ROS). Although a role of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) in DNA double-strand break repair is established, it is unclear how these proteins function in response to selenium-induced oxidative stress and senescence induction. In this study, we demonstrated that pretreating normal human diploid fibroblasts with DNA-PK kinase inhibitor NU 7026 suppressed selenium-induced senescence response. Selenium treatment induced phosphorylation of DNA-PKcs on Thr-2647 and Ser-2056, the extent of which was decreased in the presence of ATM kinase inhibitor KU 55933 or the antioxidants N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl. In contrast, the selenium-induced phosphorylation of ATM on Ser-1981 was not affected by NU 7026. Cells deficient in DNA-PKcs or pretreated with NU 7026 or N-acetylcysteine were defective in selenite-induced ROS formation. Taken together, these results indicate a distinct role of DNA-PKcs, in which this kinase can respond to and feed forward selenium-induced ROS formation and is placed downstream of ATM in the resultant senescence response.

KW - ATM

KW - DNA-PK

KW - Selenium

KW - Senescence

UR - http://www.scopus.com/inward/record.url?scp=84876792708&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876792708&partnerID=8YFLogxK

U2 - 10.1016/j.jnutbio.2012.04.011

DO - 10.1016/j.jnutbio.2012.04.011

M3 - Article

VL - 24

SP - 781

EP - 787

JO - Journal of Nutritional Biochemistry

JF - Journal of Nutritional Biochemistry

SN - 0955-2863

IS - 5

ER -