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Titolo:
X-ray induction of microsatellite instability at autosomal loci in human lymphoblastoid WTK1 cells
Autore:
Romney, CA; Paulauskis, JD; Little, JB;
Indirizzi:
Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, Radiobiol Lab, Boston, MA 02115 USA Harvard Univ Boston MA USA 02115 iol, Radiobiol Lab, Boston, MA 02115 USA Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA Harvard Univ Boston MA USA 02115 Dept Environm Hlth, Boston, MA 02115 USA
Titolo Testata:
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
fascicolo: 1-2, volume: 478, anno: 2001,
pagine: 97 - 106
SICI:
1386-1964(20010701)478:1-2<97:XIOMIA>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
POLYMERASE CHAIN-REACTION; LINKAGE MAP; REPEAT POLYMORPHISMS; MUTATOR PHENOTYPE; P53 STATUS; MUTATIONS; CANCER; LINES; TUMORIGENESIS; CHROMOSOME-16;
Keywords:
genomic instability; microsatellite repeats; human lymphoblastoid cell;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Little, JB Harvard Univ, Sch Publ Hlth, Dept Canc Cell Biol, Radiobiol Lab, 665 Huntington Ave, Boston, MA 02115 USA Harvard Univ 665 Huntington Ave Boston MA USA 02115 A 02115 USA
Citazione:
C.A. Romney et al., "X-ray induction of microsatellite instability at autosomal loci in human lymphoblastoid WTK1 cells", MUT RES-F M, 478(1-2), 2001, pp. 97-106

Abstract

Many models of carcinogenesis posit that multiple genetic events are required for a normal cell to become cancerous. As the mutation rate of a singlegene is in the range of 10(-8) to 10(-5) per cell division, a central question remains, how does a single cell acquire multiple mutations? One hypothesis, originally articulated by Loeb [10], proposed that some mutations maynot be isolated events, but are associated with a mutator phenotype that leads to the occurrence of additional mutations elsewhere in the cellular genome. To test this hypothesis, we utilized a human lymphoblastoid cell line(WTK1) that is known to be hypermutable at the autosomal thymidine kinase (TK) locus. We isolated 139 independent clones which were selected for new TK mutations that arose either spontaneously or as the result of a single X-ray exposure of 1.5 Gy. These clones were examined for second-site alterations in several microsatellite loci scattered throughout the genome using polymerase chain reaction (PCR) amplification followed by both denaturing gel electrophoresis and single-stranded conformational polymorphism (SSCP) analysis. Of these clones, 21 exhibited second-site mutations primarily involving loss of heterozygosity, 17 arose from irradiated cells whereas the remaining four arose from non-irradiated cells. We further examined the 17 clones which exhibited alterations specifically at the D16S265 locus; alterations at this site were associated with an enhanced frequency of mutations atother loci in the same region of chromosome 16q, but were not associated with additional mutations at other sites in the genome. Furthermore, new mutations arose in loci on 16q when these clones were propagated for 6 months in culture. Overall, these results support the hypothesis that radiation can induce a type of genetic instability which may facilitate the occurrence of multiple mutations throughout the genome in a small population of exposed cells. Furthermore, some cells may possess localized regions in the genome which are highly sensitive to the induction of instability. (C) 2001 Elsevier Science B.V. Ail rights reserved.

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Documento generato il 13/07/20 alle ore 05:05:13