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Titolo:
Base excision repair intermediates as topoisomerase II poisons
Autore:
Wilstermann, AM; Osheroff, N;
Indirizzi:
Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA VanderbiltUniv Nashville TN USA 37232 t Biochem, Nashville, TN 37232 USA Vanderbilt Univ, Sch Med, Dept Med Hematol Oncol, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 tol Oncol, Nashville, TN 37232 USA
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 49, volume: 276, anno: 2001,
pagine: 46290 - 46296
SICI:
0021-9258(200112)276:49<46290:BERIAT>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
MEDIATED DNA CLEAVAGE; APURINIC APYRIMIDINIC SITES; ANTICANCER DRUGS; MAMMALIAN-CELLS; TARGETED DRUGS; ABASIC SITES; CHROMOSOMAL-ABERRATIONS; DEOXYRIBONUCLEIC-ACID; SPONTANEOUS MUTATION; ESCHERICHIA-COLI;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
70
Recensione:
Indirizzi per estratti:
Indirizzo: Osheroff, N Vanderbilt Univ, Sch Med, Dept Biochem, 654 Robinson Res Bldg,Nashville, TN 37232 USA Vanderbilt Univ 654 Robinson Res Bldg Nashville TNUSA 37232 A
Citazione:
A.M. Wilstermann e N. Osheroff, "Base excision repair intermediates as topoisomerase II poisons", J BIOL CHEM, 276(49), 2001, pp. 46290-46296

Abstract

Abasic sites are the most commonly formed DNA lesions in the cell and are produced by numerous endogenous and environmental insults. In addition, they are generated by the initial step of base excision repair (BER). When located within a topoisomerase II DNA cleavage site, "intact" abasic sites actas topoisomerase II poisons and dramatically stimulate enzyme-mediated DNAscission. However, most abasic sites in cells are not intact. They exist as processed BER intermediates that contain DNA strand breaks proximal to the damaged residue. When strand breaks are located within a topoisomerase IIDNA cleavage site, they create suicide substrates that are not religated readily by the enzyme and can generate permanent double-stranded DNA breaks. Consequently, the effects of processed abasic sites on DNA cleavage by human topoisomerase II alpha were examined. Unlike substrates with intact abasic sites, model BER intermediates containing 5'- or 3'-nicked abasic sites or deoxyribosephosphate flaps were suicide substrates. Furthermore, abasic sites flanked by 5'- or 3'-nicks were potent topoisomerase II poisons, enhancing DNA scission similar to 10-fold compared with corresponding nicked oligonucleotides that lacked abasic sites. These findings suggest that topoisomerase II is able to convert processed BER intermediates to permanent double-stranded DNA breaks.

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Documento generato il 04/07/20 alle ore 20:36:26