Epigenetic displacement of HP1 from heterochromatin by HIV-1 Vpr causes premature sister chromatid separation

Mari Shimura; Yusuke Toyoda; Kenta Iijima; Masanobu Kinomoto; Kenzo Tokunaga; Kinya Yoda; Mitsuhiro Yanagida; Tetsutaro Sata; Yukihito Ishizaka

doi:10.1083/jcb.201010118

Epigenetic displacement of HP1 from heterochromatin by HIV-1 Vpr causes premature sister chromatid separation

J Cell Biol. 2011 Sep 5;194(5):721-35. doi: 10.1083/jcb.201010118. Epub 2011 Aug 29.

Authors

Mari Shimura¹, Yusuke Toyoda, Kenta Iijima, Masanobu Kinomoto, Kenzo Tokunaga, Kinya Yoda, Mitsuhiro Yanagida, Tetsutaro Sata, Yukihito Ishizaka

Affiliation

¹ Department of Intractable Diseases, Research Institute, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655, Japan. mshimura@ri.ncgm.go.jp

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anacardic Acids / pharmacology
Aneuploidy
Aurora Kinases
Autoantigens / metabolism
Cell Cycle Proteins / metabolism
Cell Line
Centromere / metabolism
Centromere Protein A
Chondroitin Sulfate Proteoglycans / metabolism
Chromatids / drug effects
Chromatids / metabolism*
Chromatin / metabolism
Chromobox Protein Homolog 5
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism*
Chromosome Segregation / physiology*
Cohesins
DNA-Binding Proteins
Epigenesis, Genetic*
Gene Deletion
HIV-1 / genetics
HeLa Cells
Heterochromatin / metabolism*
Humans
Interphase / physiology
Kinetochores / metabolism
Lymphocytes / cytology
Lymphocytes / virology
Microtubule-Associated Proteins / metabolism
Mitosis / physiology
Nuclear Proteins / metabolism
Phosphoproteins / metabolism
Protein Serine-Threonine Kinases / metabolism
Proteins / genetics
Proteins / metabolism
RNA, Small Interfering / genetics
p300-CBP Transcription Factors / antagonists & inhibitors
p300-CBP Transcription Factors / genetics
p300-CBP Transcription Factors / metabolism
vpr Gene Products, Human Immunodeficiency Virus / genetics
vpr Gene Products, Human Immunodeficiency Virus / metabolism*

Substances

Anacardic Acids
Autoantigens
CENPH protein, human
Cell Cycle Proteins
Centromere Protein A
Chondroitin Sulfate Proteoglycans
Chromatin
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Heterochromatin
INCENP protein, human
MIS12 protein, human
Microtubule-Associated Proteins
NIPBL protein, human
Nuclear Proteins
Phosphoproteins
Proteins
RAD21 protein, human
RNA, Small Interfering
SGO1 protein, human
SMC3 protein, human
structural maintenance of chromosome protein 1
vpr Gene Products, Human Immunodeficiency Virus
vpr protein, Human immunodeficiency virus 1
Chromobox Protein Homolog 5
anacardic acid
p300-CBP Transcription Factors
p300-CBP-associated factor
Aurora Kinases
Protein Serine-Threonine Kinases