Lessons from senescence: Chromatin maintenance in non-proliferating cells

Abstract

Cellular senescence is an irreversible proliferation arrest, thought to contribute to tumor suppression, proper wound healing and, perhaps, tissue and organismal aging. Two classical tumor suppressors, p53 and pRB, control cell cycle arrest associated with senescence. Profound molecular changes occur in cells undergoing senescence. At the level of chromatin, for example, senescence associated heterochromatic foci (SAHF) form in some cell types. Chromatin is inherently dynamic and likely needs to be actively maintained to achieve a stable cell phenotype. In proliferating cells chromatin is maintained in conjunction with DNA replication, but how non-proliferating cells maintain chromatin structure is poorly understood. Some histone variants, such as H3.3 and macroH2A increase as cells undergo senescence, suggesting histone variants and their associated chaperones could be important in chromatin structure maintenance in senescent cells. Here, we discuss options available for senescent cells to maintain chromatin structure and the relative contribution of histone variants and chaperones in this process. This article is part of a Special Issue entitled: Histone chaperones and chromatin assembly.

Figure 1. The multifaceted effects of cell senescence

Senescence is a well- established tumor suppression process. Senescence is likely also important for wound healing, and perhaps for generation of terminally differentiated cells in the body, highlighting the importance of senescence in normal physiology. On the darker side, senescence may also contribute to tissue aging. The secretome and senescence-associated inflammation have been proposed to contribute to tumorigenesis.

Figure 2. Structure function of SAHF

Normal proliferating cells have diffuse DAPI staining associated with euchromatin. Senescent cells form punctate foci termed SAHF, which are heterochromatic based on markers such as HP1 proteins, H3K9Me3 and hypoacetylated histones. On the one hand, SAHF might contribute to tumor suppression via repression of proliferating promoting genes such as cyclin A. On the other hand, SAHF may dampen the DNA damage response, suppress apoptosis and promote viability of senescent cells.

Figure 3. Some options available for chromatin regulation and maintenance in senescence

Multiple histone chaperones and some histone variants, e.g. H3.3, converge on PML bodies and help in formation of SAHF and chromatin maintenance. Other histone variants such as macroH2A also get incorporated into SAHF and may contribute to maintenance of chromatin structure in senescenc Finally e chromatin can also be maintained in senescent cells in conjunction with ongoing transcription and DNA repair, processes that depend on turnover of chromatin.