Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging

Abstract

Cellular senescence is an important tumor suppression process, and a possible contributor to tissue aging. Senescence is accompanied extensive changes in chromatin structure. In particular, many senescent cells accumulate specialized domains of facultative heterochromatin, called Senescence Associated Heterochromatin Foci (SAHF), which are thought to repress expression of proliferationpromoting genes, thereby contributing to senescence-associated proliferation arrest. This article reviews our current understanding of the structure, assembly and function of these SAHF at a cellular level. The possible contribution of SAHF to tumor suppression and tissue aging is also critically discussed.

The essence of senescence: Figure 1.

“…An essential step in the initiation phase of chromosome condensation appears to be the translocation of HIRA (a histone chaperone) to PML (promyelocytic leukemia nuclear) bodies (Zhang et al 2005;Adams 2007Adams , 2009). These subnuclear organelles are thought to serve as a staging ground for the formation of HIRA/ASF1A-containing complexes, which are subsequently incorporated into chromatin and play an essential role in instigating SAHF formation.…”

Many roads lead to oncogene-induced senescence

“…However, there is an impressive body of evidence suggesting that the 'irreversibility' of senescence may be mediated by dramatic changes in chromatin through the formation of 'senescence-associated heterochromatic foci' (SAHFs; Narita et al, 2003). SAHFs accumulate during oncogene-induced senescence through a multi-step process and are thought to suppress stably the expression of E2F target genes via the recruitment of Rb and heterochromatin proteins (Narita et al, 2003;Adams et al, 2007). Recently, the high-mobility group A proteins have been shown to be essential components of SAHFs and when inactivated, along with p16, result in a bypass of Ras-induced senescence in some cell types (Narita et al, 2006).…”

Heterochromatin and its Relationship to Cell Senescence and Cancer Therapy

“…A more detailed review of SAHF can be found elsewhere. 34 The purpose of this article is to discuss two provocative ideas that emerged from our studies of SAHF.…”