Senescent cells assemble specialized structures called senescence-associated heterochromatic foci (SAHF). Heterochromatin is considered to be transcriptionally inactive, and SAHF contain genes associated with cell growth that are essentially switched off. "It seems likely that incorporation of proliferation-associated genes into heterochromatin could contribute to the irreversible cell cycle arrest characteristic of senescence. We are interested in defining the molecular events leading to these changes in chromatin structure in senescent cells," explains study leader Dr. Peter D. Adams from the Fox Chase Cancer Center in Philadelphia.
Dr. Adams and colleagues found that the histone macroH2A is specifically enriched in SAHF. Histones are proteins that are associated with chromatin structure. The researchers also demonstrated that HIRA and ASF1a, two known regulators of chromatin structure, play a key role in formation of SAHF. When human cells were genetically manipulated to activate HIRA and ASF1a, the cells assembled SAHF and showed markers for senescence. If ASF1a was reduced, there was a profound decrease in the number of cells with macroH2A-containing SAHF. These data link changes in cell proliferation to alterations in chromatin structure.
"Together, these observations show that ASF1a promotes and is required for efficient senescence-associated cell cycle exit and support the notion that HIRA/ASF1a-mediated formation of SAHF directly contributes to cell cycle exit during senescence," concludes Dr. Adams. The researchers speculate that alterations of HIRA and ASF1a might contribute to a failure to exit the cell cycle and possibly to the development of cancer. Future studies will investigate this possibility.
Rugang Zhang, Maxim V. Poustovoitov, Xiaofen Ye, Hidelita A. Santos, Wei Chen, Sally M. Daganzo, Jan P. Erzberger, Ilya G. Serebriiskii, Adrian A. Canutescu, Roland L. Dunbrack, John R. Pehrson, James M. Berger, Paul D. Kaufman, and Peter D. Adams: "Formation of macroH2A-Containing Senescence-Associated Heterochromatin Foci and Senescence Driven by ASF1a and HIRA"
The other members of the research team include Rugang Zhang, Xiaofen Ye, Hidelita A. Santos, Wei Chen, Ilya G. Serebriiskii, Adrian A. Canutescu, and Roland L. Dunbrack, of Fox Chase Cancer Center; Maxim V. Poustovoitov of Fox Chase Cancer Center and Russian State Medical University; Sally M. Daganzo and Paul D. Kaufman of Lawrence Berkeley National Laboratory and University of California, Berkeley; Jan P. Erzberger and James M. Berger of Lawrence Berkeley National Laboratory; and John R. Pehrson of University of Pennsylvania School of Veterinary Medicine. 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).
Publishing in Developmental Cell, Volume 8, Number 1, January 2005, pages 19–30. www.developmentalcell.com/
Journal
Developmental Cell