title: Epigenetic displacement of HP1 from heterochromatin by HIV-1 Vpr causes premature sister chromatid separation.
abstract: Although pericentromeric heterochromatin is essential for chromosome segregation, its role in humans remains controversial. Dissecting the function of HIV-1-encoded Vpr, we unraveled important properties of heterochromatin during chromosome segregation. In Vpr-expressing cells, hRad21, hSgo1, and hMis12, which are crucial for proper chromosome segregation, were displaced from the centromeres of mitotic chromosomes, resulting in premature chromatid separation (PCS). Interestingly, Vpr displaced heterochromatin protein 1-α (HP1-α) and HP1-γ from chromatin. RNA interference (RNAi) experiments revealed that down-regulation of HP1-α and/or HP1-γ induced PCS, concomitant with the displacement of hRad21. Notably, Vpr stimulated the acetylation of histone H3, whereas p300 RNAi attenuated the Vpr-induced displacement of HP1-α and PCS. Furthermore, Vpr bound to p300 that was present in insoluble regions of the nucleus, suggesting that Vpr aberrantly recruits the histone acetyltransferase activity of p300 to chromatin, displaces HP1-α, and causes chromatid cohesion defects. Our study reveals for the first time centromere cohesion impairment resulting from epigenetic disruption of higher-order structures of heterochromatin by a viral pathogen.
authors.affiliation: Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655, Japan. mshimura@ri.ncgm.go.jp
authors.forename: Mari
authors.initials: M
authors.lastname: Shimura
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Kenta
authors.initials: K
authors.lastname: Iijima
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kinomoto
authors.forename: Kenzo
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Kinya
authors.initials: K
authors.lastname: Yoda
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yanagida
authors.forename: Tetsutaro
authors.initials: T
authors.lastname: Sata
authors.forename: Yukihito
authors.initials: Y
authors.lastname: Ishizaka
mesh_terms: D048729:Anacardic Acids / Q000494:pharmacology; D000782:Aneuploidy; D064127:Aurora Kinases; D001324:Autoantigens / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002503:Centromere / Q000378:metabolism; D000076247:Centromere Protein A; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D002842:Chromatids / Q000187:drug effects / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D020090:Chromosome Segregation / Q000502:physiology*; D004268:DNA-Binding Proteins; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D015497:HIV-1 / Q000235:genetics; D006367:HeLa Cells; D006570:Heterochromatin / Q000378:metabolism*; D006801:Humans; D007399:Interphase / Q000502:physiology; D018386:Kinetochores / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000821:virology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008938:Mitosis / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D000097722:Cohesins; D000098550:Structural Maintenance of Chromosome Protein 1; D000099224:p300-CBP-Associated Factor
chemical_list: D048729:Anacardic Acids; D064127:Aurora Kinases; D001324:Autoantigens; D018797:Cell Cycle Proteins; D000076247:Centromere Protein A; D011508:Chondroitin Sulfate Proteoglycans; D002843:Chromatin; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006570:Heterochromatin; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011506:Proteins; D034741:RNA, Small Interfering; D050880:p300-CBP Transcription Factors; D054325:vpr Gene Products, Human Immunodeficiency Virus; D000097722:Cohesins; D000098550:Structural Maintenance of Chromosome Protein 1; D000099224:p300-CBP-Associated Factor; C121933:CENPH protein, human; C083767:INCENP protein, human; C492664:MIS12 protein, human; C487465:NIPBL protein, human; C429022:RAD21 protein, human; C496644:SGO1 protein, human; C492318:SMC3 protein, human; C514912:vpr protein, Human immunodeficiency virus 1; C088115:anacardic acid