title: Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection.
abstract: Sirtuins are NAD-dependent deacetylases that sense oxidative stress conditions and promote a protective cellular response. The Sirtuin SirT1 is involved in facultative heterochromatin formation through an intimate functional relationship with the H3K9me3 methyltransferase Suv39h1, a chromatin organization protein. However, SirT1 also regulates Suv39h1-dependent constitutive heterochromatin (CH) through an unknown mechanism; interestingly, SirT1 does not significantly localize in these regions. Herein, we report that SirT1 controls global levels of Suv39h1 by increasing its half-life through inhibition of Suv39h1 lysine 87 polyubiquitination by the E3-ubiquitin ligase MDM2. This in turn increases Suv39h1 turnover in CH and ensures genome integrity. Stress conditions that lead to SirT1 upregulation, such as calorie restriction, also induce higher levels of Suv39h1 in a SirT1-dependent manner in vivo. These observations reflect a direct link between oxidative stress response and Suv39h1 and support a dynamic view of heterochromatin, in which its structure adapts to cell physiology.
authors.affiliation: Chromatin Biology Laboratory, Cancer Epigenetics and Biology Program, Institut d'Investigació Biomèdica de Bellvitge, Avinguda Gran Via de l'Hospitalet 199-203, 08907 L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Laia
authors.initials: L
authors.lastname: Bosch-Presegué
authors.forename: Helena
authors.initials: H
authors.lastname: Raurell-Vila
authors.forename: Anna
authors.initials: A
authors.lastname: Marazuela-Duque
authors.forename: Noriko
authors.initials: N
authors.lastname: Kane-Goldsmith
authors.forename: Adamo
authors.initials: A
authors.lastname: Valle
authors.forename: Jordi
authors.initials: J
authors.lastname: Oliver
authors.forename: Lourdes
authors.initials: L
authors.lastname: Serrano
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vaquero
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D031204:Caloric Restriction; D042002:Chromatin Assembly and Disassembly; D004795:Enzyme Stability; D042822:Genomic Instability; D057809:HEK293 Cells; D006207:Half-Life; D006367:HeLa Cells; D006570:Heterochromatin / Q000378:metabolism*; D006801:Humans; D008239:Lysine; D008297:Male; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D041681:NIH 3T3 Cells; D018384:Oxidative Stress; D025821:Polyubiquitin / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination
chemical_list: D006570:Heterochromatin; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D025821:Polyubiquitin; C407843:SUV39H1 protein, human; C498700:Suv39h1 protein, mouse; C512117:Suv39h1 protein, rat; D008780:Methyltransferases; D051736:Proto-Oncogene Proteins c-mdm2; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D008239:Lysine