title: The tumor suppressor SirT2 regulates cell cycle progression and genome stability by modulating the mitotic deposition of H4K20 methylation.
abstract: The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G2/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1-3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle.
authors.affiliation: Department of Genetics, the Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey 08854, USA. serrano@biology.rutgers.edu
authors.forename: Lourdes
authors.initials: L
authors.lastname: Serrano
authors.forename: Paloma
authors.initials: P
authors.lastname: Martínez-Redondo
authors.forename: Anna
authors.initials: A
authors.lastname: Marazuela-Duque
authors.forename: Berta N
authors.initials: BN
authors.lastname: Vazquez
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Dooley
authors.forename: Philipp
authors.initials: P
authors.lastname: Voigt
authors.forename: David B
authors.initials: DB
authors.lastname: Beck
authors.forename: Noriko
authors.initials: N
authors.lastname: Kane-Goldsmith
authors.forename: Qiang
authors.initials: Q
authors.lastname: Tong
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Rabanal
authors.forename: Dolors
authors.initials: D
authors.lastname: Fondevila
authors.forename: Purificación
authors.initials: P
authors.lastname: Muñoz
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vaquero
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D055786:Gene Knockout Techniques; D042822:Genomic Instability; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D011485:Protein Binding; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; C474199:SIRT2 protein, human; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2