Cited by 804Telomeres, Telomerase, and SenescenceCancer-related Molecular PathwaysGenetics, Aging, and Longevity in Model Organisms

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Bypass of Senescence After Disruption of p21 CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts

Brown, Jeremy P., Wei, Wenyi, Sedivy, John M.·1997·Science

DOI 10.1126/science.277.5327.831

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Abstract

Most somatic cells die after a finite number of cell divisions, a phenomenon described as senescence. The p21 CIP1/WAF1 gene encodes an inhibitor of cyclin-dependent kinases. Inactivation of p21 by two sequential rounds of targeted homologous recombination was sufficient to bypass senescence in normal diploid human fibroblasts. At the checkpoint between the prereplicative phase of growth and the phase of chromosome replication, cells lacking p21 failed to arrest the cell cycle in response to DNA damage, but their apoptotic response and genomic stability were unaltered. These results establish the feasibility of using gene targeting for genetic studies of normal human cells.

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Authors: Brown, J. P., Wei, W., & Sedivy, J. M.
Affiliations: Brown University (US)
Corresponding author: Brown, Jeremy P.
Sedivy, John M.
ORCID: Brown, Jeremy P.
Wei, Wenyi
Sedivy, John M.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 1997-08-08
Volume: 277
Issue: 5327
Pages: 831-834
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.277.5327.831
OpenAlex: W1992934869
Cited by: 804
References: 31
Citations by year: 2026: 6 · 2025: 5 · 2024: 7 · 2023: 8 · 2022: 19 · 2021: 17 · 2020: 13 · 2019: 17 · 2018: 22 · 2017: 16 · 2016: 30 · 2015: 20 · 2014: 29 · 2013: 36 · 2012: 28
FWCI: 26.34
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of General Medical Sciences (GM 41690, R01GM041690)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords: cellular senescence, p21 CIP1/WAF1, cyclin-dependent kinase inhibitors, homologous recombination, gene targeting, human diploid fibroblasts, DNA damage checkpoint, cell cycle arrest, apoptosis, genome stability, cell immortalization
MeSH terms: Aspartate Carbamoyltransferase, Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing), Cell Division, Cells, Cultured, Dihydroorotase, DNA Damage, Fibroblasts, Genetic Vectors, Humans, Multienzyme Complexes, G1 Phase, Cyclins, Telomere, Cellular Senescence, Apoptosis, Gene Deletion, Electroporation, Gene Targeting, Cyclin-Dependent Kinase Inhibitor p21

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Bypass of Senescence After Disruption of p21 CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts

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