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RESEARCH PAPER
1 Division of Pediatric Oncology, and 2 Division of Experimental Therapeutics, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA; 3 Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA; 4 Calcium Research Laboratory, Department of Medicine, McGill University, Royal Victoria Hospital, Montreal, Quebec, H3A 1A1, Canada; 5 Department of Comparative Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
Imperfect maintenance of genome integrity has been postulated to be an important cause of aging. Here we provide support for this hypothesis by demonstrating that the disruption of PASG (lsh), a SNF2-like factor that facilitates DNA methylation, causes global hypomethylation, developmental growth retardation and a premature aging phenotype. PASG mutant mice display signs of growth retardation and premature aging, including low birth weight, failure to thrive, graying and loss of hair, reduced skin fat deposition, osteoporosis, kyphosis, cachexia, and premature death. Fibroblasts derived from PASG mutant embryos show a replicative senescence phenotype. Both PASG mutant mice and fibroblasts demonstrate a markedly increased expression of senescence-associated tumor suppressor genes, such as p16INK4a, that is independent of promoter methylation, but, instead, is associated with down-regulation of bmi-1, a negative regulator of p16INK4a. These studies show that PASG is essential for properly maintaining DNA methylation and gene expression patterns that are required for normal growth and longevity. PASG mutant mice provide a useful model for the study of aging as well as the mechanisms regulating epigenetic patterning during development and postnatal life.
[Keywords: PASG; lsh; SMARCA6; methylation; genomic instability; aging; senescence]
Received December 8, 2003; revised version accepted March 22, 2004.
6 Corresponding author.
E-MAIL arcecro{at}jhmi.edu; FAX (410) 502-7223.
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