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 by 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 proliferation-promoting 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.

Figure 1. Formation of SAHF in senescent human cells is linked to HIRA’s localization to PML nuclear bodies

Senescent human WI38 cells were stained with antibodies to HIRA (red), PML (green) and with DAPI to visualize DNA (blue). Yellow foci result from colocalization of HIRA and PML in PML nuclear bodies. SAHF is evident in the uneven distribution of DNA through the nucleus.

Figure 2. A model for formation of SAHF in senescent human cells

Senescence is triggered by short telomeres, activated oncogenes and other cell stresses. The HIRA/ASF1a pathway cooperates with the p16INK4a/pRB pathway to drive chromosome condensation. The mode of activation of HIRA/ASF1a and p16INK4a are largely unknown. After chromosome condensation, HP1 proteins and histone variant macroH2A are incorporated into SAHF. Recruitment of HP1γ to SAHF depends on HP1γ phosphorylation. Dashed lines indicate steps that are poorly defined at present. See text and references for further details.