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001-es BibID:	BIBFORM047646
035-os BibID:	PMID:16298690
Első szerző:	Bácsi Attila (immunológus)
Cím:	Modulation of DNA-dependent protein kinase activity in chlorambucil-treated cells / Attila Bacsi, Subbaraj Kannan, Myung-Soog Lee, Tapas K. Hazra, Istvan Boldogh
Dátum:	2005
ISSN:	0891-5849
Megjegyzések:	DNA-dependent protein kinase (DNA-PK) is activated in a two-step process whereby the Ku heterodimer first binds to the DNA double-strandbreaks (dsbs) and then the DNA-PK catalytic subunit (cs) is recruited to form a repair complex. Oxidative stress is simultaneously generated alongwith DNA damage by ionizing radiation or chemotherapeutic agents whose impact on the DNA-PK activity has not previously been investigated.Here we show that the DNA damage-induced kinase activity of DNA-PK was modulated by oxidative stress, which was induced along with DNAdsbs in chlorambucil (Cbl)-exposed cells. Pretreatment with the antioxidants, 2(3)-t-butyl-4-hydroxyanisole or N-acetyl-l-cysteine enhanced theamount of DNA-PKcs phosphorylated at threonine 2609 (DNA-PKpThr2609) at the DNA dsbs and DNA-PK activity. Conversely, oxidative stressinduced by l-buthionine (SR)-sulfoximine or glucose oxidase decreased the DNA-PK activity in Cbl-exposed cells. In addition, DNA-PKpThr2609was poorly detectable at the site of DNA dsbs, as shown by colocalization to DNA-end-binding pH2AX or p53BP1. There was no change in theprotein levels of DNA-PKcs, Ku70, or Ku86. Data from these studies provide the first evidence that oxidative stress effects posttranslationalmodification and assembly of DNA-PK complex at DNA dsbs, and thereby repair of DNA dsbs.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban Oxidative stress DNA-PK DNA dsbs repair Free radicals
Megjelenés:	Free Radical Biology and Medicine. - 39 : 12 (2005), p. 1650-1659. -
További szerzők:	Kannan, Subbaraj Myung-Soog, Lee Hazra, Tapas K. Boldogh István
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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001-es BibID:	BIBFORM047643
035-os BibID:	PMID:14599773
Első szerző:	Boldogh István
Cím:	Reduced DNA double strand breaks in chlorambucil resistant cells are related to high DNA-PKcs activity and low oxidative stress / Istvan Boldogh, Gargi Roy, Myung-Soog Lee, Attila Bacsi, Tapas K. Hazra, Kishor K. Bhakat, Gokul C. Das, Sankar Mitra
Dátum:	2003
ISSN:	0300-483X
Megjegyzések:	Modulation of DNA repair represents a strategy to overcome acquired drug resistance of cells to genotoxic chemotherapeuticagents, including nitrogen mustards (NM). These agents induce DNA inter-strand cross-links, which in turn produce doublestrand breaks (dsbs). These breaks are primarily repaired via the nonhomologous end-joining (NHEJ) pathway.ADNA-dependentprotein kinase (DNA-PK) complex plays an important role in NHEJ, and its increased level/activity is associated with acquireddrug resistance of human tumors. We show in this report that the DNA-PK complex has comparable levels and kinase activityof DNA-PK catalytic subunit (DNA-PKcs) in a nearly isogenic pair of drug-sensitive (A2780) and resistant (A2780/100) cells;however, treatment with chlorambucil (Cbl), a NM-type of drug, induced differential effects in these cells. The kinase activityof DNA-PKcs was increased up to 2 h after Cbl treatment in both cell types; however, it subsequently decreased only in sensitivecells, which is consistent with increased levels of DNA dsbs. The decreased kinase activity of DNA-PKcs was not due to a changein its amount or the levels ofKu70 andKu86, their subcellular distribution, cell cycle progression or caspase-mediated degradationof DNA-PK. In addition to DNA cross-links, Cbl treatment of cells causes a 2.2-fold increase in the level of reactive oxygenspecies (ROS) in both cell types. However, the ROS in A2780/100 cells were reduced to the basal level after 3?4 h, while sensitivecells continued to produce ROS and undergo apoptosis. Pre-treatment of A2780 cells with the glutathione (GSH) precursor,N-acetyl-l-cysteine prevented Cbl-induced increase in ROS, augmented the kinase activity of DNA-PKcs, decreased the levelsof DNA dsbs and increased cell survival. Depletion in GSH from A2780/100 cells by l-buthionine sulfoximine (BSO) resulted insustained production of ROS, loweredDNA-PKcs kinase activity, enhanced levels ofDNAdsbs, and increased cell killing by Cbl.We propose that oxidative stress decreases repair of DNA dsbs via lowering kinase activity of DNA-PKcs and that induction ofROS could be the basis for adjuvant therapies for sensitizing tumor cells to nitrogen mustards and other DNA cross-linking drugs.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban Oxidative stress DNA-PK DNA double strand breaks
Megjelenés:	Toxicology. - 193 : 1-2 (2003), p. 137-152. -
További szerzők:	Roy, Gargi Myung-Soog, Lee Bácsi Attila (1967-) (immunológus) Hazra, Tapas K. Bhakat, Kishor K. Das, Gokul C. Mitra, Sankar
Internet cím:	Szerző által megadott URL DOI Intézményi repozitóriumban (DEA) tárolt változat
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