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Mol. Cell. Biol. doi:10.1128/MCB.02019-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Molecular Dissection of Formation of Senescent Associated Heterochromatin Foci

Department of Basic Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111

^* To whom correspondence should be addressed. Email: peter.adams{at}fccc.edu.

	Abstract

Senescence is characterized by an irreversible cell proliferation arrest. Specialized domains of facultative heterochromatin, called Senescence Associated Heterochromatin Foci (SAHF), are thought to contribute to the irreversible cell cycle exit in many senescent cells, by repressing expression of proliferation-promoting genes such as cyclin A. SAHF contain known heterochromatin-forming proteins, such as Heterochromatin Protein 1 (HP1) and histone H2A variant macroH2A, and other specialized chromatin proteins, such as HMGA proteins. Previously, we showed that a complex of histone chaperones, HIstone Repressor A (HIRA) and Anti-Silencing Function 1a (ASF1a), play a key role in formation of SAHF. Here we have further dissected apart the series of events that contribute to SAHF formation. We show that each chromosome condenses into a single SAHF focus. Chromosome condensation depends on the ability of ASF1a to physically interact with its deposition substrate, histone H3, in addition to its co-chaperone, HIRA. In cells entering senescence, HP1, but not the related proteins HP1 and HP1, becomes phosphorylated on serine 93. This phosphorylation is required for efficient incorporation of HP1 into SAHF. Remarkably, however, a dramatic reduction in the amount of chromatin-bound HP1 proteins does not detectably affect chromosome condensation into SAHF. Moreover, abundant HP1 proteins are not required for accumulation in SAHF of histone H3 methylated on lysine 9, recruitment of macroH2A proteins, nor other hallmarks of senescence, such as expression of senescence-associated -galactosidase activity and senescence-associated cell cycle exit. Based on our results we propose a step-wise model for formation of SAHF.

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