Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA.
In senescent cells, specialized domains of transcriptionally silent senescence-associated heterochromatic foci (SAHF), containing heterochromatin proteins such as HP1, are thought to repress expression of proliferation-promoting genes. We have investigated the composition and mode of assembly of SAHF and its contribution to cell cycle exit. SAHF is enriched in a transcription-silencing histone H2A variant, macroH2A. As cells approach senescence, a known chromatin regulator, HIRA, enters PML nuclear bodies, where it transiently colocalizes with HP1 proteins, prior to incorporation of HP1 proteins into SAHF. A physical complex containing HIRA and another chromatin regulator, ASF1a, is rate limiting for formation of SAHF and onset of senescence, and ASF1a is required for formation of SAHF and efficient senescence-associated cell cycle exit. These data indicate that HIRA and ASF1a drive formation of macroH2A-containing SAHF and senescence-associated cell cycle exit, via a pathway that appears to depend on flux of heterochromatic proteins through PML bodies.
Zhang
Rugang
R
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Poustovoitov
Maxim V
MV
Ye
Xiaofen
X
Santos
Hidelita A
HA
Chen
Wei
W
Daganzo
Sally M
SM
Erzberger
Jan P
JP
Serebriiskii
Ilya G
IG
Canutescu
Adrian A
AA
Dunbrack
Roland L
RL
Pehrson
John R
JR
Berger
James M
JM
Kaufman
Paul D
PD
Adams
Peter D
PD
D000595:Amino Acid Sequence; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004303:Dosage Compensation, Genetic; D005786:Gene Expression Regulation / Q000502:physiology; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation / Q000379:methods; D007211:Indoles; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection / Q000379:methods; D025521:Tumor Suppressor Proteins; D018631:ras Proteins / Q000378:metabolism
C491641:ASF1A protein, human; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D006657:Histones; D007211:Indoles; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C120756:macroH2A histone; D000090266:Chromobox Protein Homolog 5; C007293:DAPI; D018631:ras Proteins