Scientists have identified specific cellular events that enable a cell to make the transition from a state of active growth to an irreversible state of growth arrest, called senescence. Understanding the mysterious process of senescence is of great importance to human biology, because a failure to enter this normal stage in the life cycle of a cell may lead to uncontrolled growth and cellular immortality, the hallmark of cancer. The research is published in the January issue of Developmental Cell.
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"
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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