title: Altered telomere homeostasis and resistance to skin carcinogenesis in Suv39h1 transgenic mice.
abstract: The Suv39h1 and Suv39h2 H3K9 histone methyltransferases (HMTs) have a conserved role in the formation of constitutive heterochromatin and gene silencing. Using a transgenic mouse model system we demonstrate that elevated expression of Suv39h1 increases global H3K9me3 levels in vivo. More specifically, Suv39h1 overexpression enhances the imposition of H3K9me3 levels at constitutive heterochromatin at telomeric and major satellite repeats in primary mouse embryonic fibroblasts. Chromatin compaction is paralleled by telomere shortening, indicating that telomere length is controlled by H3K9me3 density at telomeres. We further show that increased Suv39h1 levels result in an impaired clonogenic potential of transgenic epidermal stem cells and Ras/E1A transduced transgenic primary mouse embryonic fibroblasts. Importantly, Suv39h1 overexpression in mice confers resistance to a DMBA/TPA induced skin carcinogenesis protocol that is characterized by the accumulation of activating H-ras mutations. Our results provide genetic evidence that Suv39h1 controls telomere homeostasis and mediates resistance to oncogenic stress in vivo. This identifies Suv39h1 as an interesting target to improve oncogene induced senescence in premalignant lesions.
authors: a Laboratorio Nazionale CIB (LNCIB) - Area Science Park ; Trieste , Italy.
authors: Eleonora
authors: E
authors: Petti
authors: Fabian
authors: F
authors: Jordi
authors: Valentina
authors: V
authors: Buemi
authors: Roberto
authors: R
authors: Dinami
authors: Roberta
authors: R
authors: Benetti
authors: Maria A
authors: MA
authors: Blasco
authors: Stefan
authors: S
authors: Schoeftner
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004817:Epidermis / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009154:Mutation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D016615:Telomere / Q000378:metabolism*; D059505:Telomere Homeostasis; D059506:Telomere Shortening; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C096188:Cbx1 protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D012097:Repressor Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; C498700:Suv39h1 protein, mouse; D008780:Methyltransferases; D018631:ras Proteins
keywords: Suv39h HMTase; carcinogenesis; chromatin; telomere length; telomeres