TY - JOUR
T1 - Formation of macroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA
AU - Zhang, Rugang
AU - Poustovoitov, Maxim V.
AU - Ye, Xiaofen
AU - Santos, Hidelita A.
AU - Chen, Wei
AU - Daganzo, Sally M.
AU - Erzberger, Jan P.
AU - Serebriiskii, Ilya G.
AU - Canutescu, Adrian A.
AU - Dunbrack, Roland L.
AU - Pehrson, John R.
AU - Berger, James M.
AU - Kaufman, Paul D.
AU - Adams, Peter D.
N1 - Funding Information:
The authors thank William Earnshaw and David Schultz for antibodies, Ken Zaret for critical reading of the manuscript, Erica Golemis for technical guidance, and Robert Weinberg for pBABE-RasV12. P.D.K. is supported by the DOE (FWP KP110301) and NSF (MCB-0234014). This research was conducted while R.Z. was a Glenn/AFAR postdoctoral fellow; R.Z. was also supported by a W.J. Avery Fellowship. J.R.P. is supported by NIH (GM-49351). J.M.B. is supported by the G. Harold and Leila Y. Mathers Foundation. P.D.A. is a Leukemia and Lymphoma Society Scholar and is also supported by the DOD (DAMD17-02-1-0726) and the NIH (R01 GM062281).
PY - 2005/1
Y1 - 2005/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.devcel.2004.10.019
DO - 10.1016/j.devcel.2004.10.019
M3 - Article
C2 - 15621527
AN - SCOPUS:19944427674
SN - 1534-5807
VL - 8
SP - 19
EP - 30
JO - Developmental Cell
JF - Developmental Cell
IS - 1
ER -