XRCC1 down-regulation in human cells leads to DNA-damaging agent hypersensitivity, elevated sister chromatid exchange, and reduced survival of BRCA2 mutant cells.

XRCC1 down-regulation in human cells leads to DNA-damaging agent hypersensitivity, elevated sister chromatid exchange, and reduced survival of BRCA2 mutant cells. Research Abstract Details 

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XRCC1 down-regulation in human cells leads to DNA-damaging agent hypersensitivity, elevated sister chromatid exchange, and reduced survival of BRCA2 mutant cells. Abstract Text:

Jinshui Fan,Paul F Wilson,Heng-Kuan Wong,Salustra S Urbin,Larry H Thompson,David M Wilson,

Previous studies using rodent cells indicate that a deficiency in XRCC1 results in reduced single-strand break repair, increased sensitivity to DNA-damaging agents, and elevated levels of sister chromatid exchange (SCE). Epidemiological studies have suggested an association of certain human XRCC1 polymorphisms with genetic instability and cancer susceptibility. However, investigations on the molecular functions of XRCC1 in human cells are limited. To determine the contributions of this nonenzymatic scaffold protein, we suppressed XRCC1 levels in several human cell lines using small interfering RNA (siRNA) technology. We report that XRCC1 down-regulation in HeLa cells leads to a concomitant decrease in the DNA ligase 3 protein level and an impaired nick ligation capacity. In addition, depletion of XRCC1 resulted in a significantly increased sensitivity to the alkylating agent methyl methanesulfonate and the thymidine base analog 5-hydroxymethyl-2'-deoxyuridine, a slightly increased sensitivity to ethyl methanesulfonate and 1,3-bis(2-chloroethyl)-1-nitrosourea, and no change in the response to camptothecin. We also discovered that a 70-80% reduction in XRCC1 protein leads to an elevated level of SCE in both HeLa cells and normal human fibroblasts, but does not affect chromosome aberrations in the diploid fibroblasts. Last, XRCC1 siRNA transfection led to an approximately 40% decrease in the survival of BRCA2-deficient cells, supporting a model whereby the accumulation of unrepaired SSBs leads to the accumulation of cytotoxic DNA double strand breaks following replication fork collapse in cells defective in homologous recombination.

XRCC1 down-regulation in human cells leads to DNA-damaging agent hypersensitivity, elevated sister chromatid exchange, and reduced survival of BRCA2 mutant cells. Publishing Authors By Initials

J Fan,PF Wilson,HK Wong,SS Urbin,LH Thompson,DM Wilson,

For similar investigative techniques: genetic techniques: gene transfer techniques: transfection research abstracts see: investigative techniques: genetic techniques: gene transfer techniques: transfection research

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XRCC1 down-regulation in human cells leads to DNA-damaging agent hypersensitivity, elevated sister chromatid exchange, and reduced survival of BRCA2 mutant cells. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Intr

Journal: Environmental and molecular mutagenesis

VOLUME: 48

Page Numbers: 491-500

Journal Abbreviation: Environ. Mol. Mutagen.

ISSN: 0893-6692

DAY: 3

MONTH: Jul

YEAR: 2007

XRCC1 down-regulation in human cells leads to DNA-damaging agent hypersensitivity, elevated sister chromatid exchange, and reduced survival of BRCA2 mutant cells. Information

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LANGUAGE: eng

NlmUniqueID: 8800109

XRCC1 down-regulation in human cells leads to DNA-damaging agent hypersensitivity, elevated sister chromatid exchange, and reduced survival of BRCA2 mutant cells. Keywords Mesh Terms:

KEYWORDS: Transfection

MESH TERMS: drug effects

Chemical & Substance for Abstract: XRCC1 down-regulation in human cells leads to DNA-damaging agent hypersensitivity, elevated sister chromatid exchange, and reduced survival of BRCA2 mutant cells. Information

Substance Name: Methyl Methanesulfonate

Registry Number: 66-27-3

Grant and Affiliation Information for XRCC1 down-regulation in human cells leads to DNA-damaging agent hypersensitivity, elevated sister chromatid exchange, and reduced survival of BRCA2 mutant cells.

AFFILIATION: Laboratory of Molecular Gerontology, National Institute on Aging, Baltimore, Maryland, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA11256

ACRONYM: CA

MEDLINETA: Environ Mol Mutagen

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