A deletion within the murine Werner syndrome helicase induces sensitivity to inhibitors of topoisomerase and loss of cellular proliferative capacity
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- Michel Lebel
- Department of Genetics, Harvard Medical School, and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115
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- Philip Leder
- Department of Genetics, Harvard Medical School, and Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, MA 02115
抄録
<jats:p> Werner syndrome (WS) is an autosomal recessive disorder characterized by genomic instability and the premature onset of a number of age-related diseases. The gene responsible for WS encodes a member of the RecQ-like subfamily of DNA helicases. Here we show that its murine homologue maps to murine chromosome 8 in a region syntenic with the human <jats:italic>WRN</jats:italic> gene. We have deleted a segment of this gene and created <jats:italic>Wrn</jats:italic> -deficient embryonic stem (ES) cells and WS mice. While displaying reduced embryonic survival, live-born WS mice otherwise appear normal during their first year of life. Nonetheless, although several DNA repair systems are apparently intact in homozygous WS ES cells, such cells display a higher mutation rate and are significantly more sensitive to topoisomerase inhibitors (especially camptothecin) than are wild-type ES cells. Furthermore, mouse embryo fibroblasts derived from homozygous WS embryos show premature loss of proliferative capacity. At the molecular level, wild-type, but not mutant, WS protein copurifies through a series of centrifugation and chromatography steps with a multiprotein DNA replication complex. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 95 (22), 13097-13102, 1998-10-27
Proceedings of the National Academy of Sciences
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詳細情報 詳細情報について
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- CRID
- 1360574096098738304
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- NII論文ID
- 80010676420
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- ISSN
- 10916490
- 00278424
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- データソース種別
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