Cellular senescence and chromatin organisation

British Journal of Cancer (2007) 96, 686 – 691 & 2007 Cancer Research UK All rights reserved 0007 – 0920/07 $30.00 www.bjcancer.com Review Cellular senescence and chromatin organisation M Narita*,1 1 Cancer Research UK, Cambridge Research Institute, Robinson Way, Cambridge CB2 0RE, UK Despite the potential importance of senescence in tumour suppression, its effector mechanism is poorly understood. Recent studies suggest that alterations in the chromatin environment might add an additional layer of stability to the phenotype. In this review, recent discoveries on the interplay between senescence and chromatin biology are overviewed. British Journal of Cancer (2007) 96, 686 – 691. doi:10.1038/sj.bjc.6603636 www.bjcancer.com Published online 20 February 2007 & 2007 Cancer Research UK Cellular senescence was first described as a state of permanent cell cycle arrest resulting from the replicative exhaustion of cultured normal diploid cells (Hayflick, 1965). Despite the static appearance and steady state of senescent cells, they are viable and metabolically active. Senescent cells exhibit a large and flat morphology with vacuoles, and an enlarged nucleus. Besides the morphological changes, the best-known marker is senescenceassociated b-galactosidase activity (Dimri et al, 1995). More recently it has been shown that senescence is often accompanied by specific alterations of the chromatin structure, known as senescence-associated heterochromatic foci (Narita et al, 2003). The senescence phenotype is extremely stable and, in contrast to quiescent cells (readily reversible cell cycle arrest), senescent cells are unresponsive to mitogenic stimuli such as serum or growth factors. Thus, senescence seems to be antithetical to ‘immortalisation’ in cultured cells and limits their neoplastic transformation. However, confirmation in vivo of this in vitro concept did not emerge until recently. A recent series of studies identified senescent cells in vivo using various models, thus reaffirming the significance of senescence as an intrinsic tumour suppressor pathway (Braig et al, 2005; Chen et al, 2005; Collado et al, 2005; Lazzerini Denchi et al, 2005; Michaloglou et al, 2005). Nevertheless, the molecular mechanism of senescence, particularly how senescent cells are driven into such a stable arrest, is not yet clear. To address this question, we have focused on the chromatin changes that occur during senescence and we have proposed that epigenetic regulation of gene expression might be involved in this process at least in vitro (Narita et al, 2003, 2006). Here the clinical significance of senescence as well as the role of chromatin alteration as an effector mechanism of senescence are discussed (Table 1). SENESCENCE AND AGEING Originally, cellular senescence and organismal ageing were believed to be different concepts, yet it has been suggested that they are closely related owing to their shared ability to limit ‘lifespan’. Indeed, fibroblasts isolated from older individuals or *Correspondence: Dr M Narita; E-mail: Received 19 October 2006; revised 16 January 2007; accepted 22 January 2007; published online 20 February 2007 patients with premature ageing syndrome such as Werner syndrome exhibit SA-b-gal activity earlier than those from young or healthy individuals, respectively. In addition, some senescenceassociated genes, such as p53, can influence organismal lifespan. However, a direct causative effect of cellular senescence on ageing has never been shown. Now new studies shed light on this question; senescence may play a role in suppressing age-related cancer risk at the expense of juvenescence (Janzen et al, 2006; Krishnamurthy et al, 2006; Molofsky et al, 2006). Ageing is associated with a reduction in the regenerative capacity of tissues, for which the functional progenitor cells are critical. An attractive idea is that senescence of the progenitor cells can be a cause of functional and physiological decline in tissue homeostasis and, as a consequence, individual ageing. A recent series of studies provided strong and direct insights into this senescence-ageing association (Janzen et al, 2006; Krishnamurthy et al, 2006; Molofsky et al, 2006). These reports showed that the age-dependent increase of p16 expression, an important marker as well as a mediator of cellular senescence, is associated with the limitation of self-renewal activity in the regenerative cells and contributes to ageing in bone marrow, brain and pancreatic islets (Janzen et al, 2006; Krishnamurthy et al, 2006; Molofsky et al, 2006). These studies raised the possibility that senescence of stem/ progenitor cell compartments can, at least partially, be a direct cause of organismal ageing. The expression of the p16 tumour suppressor gene might balance the age-related risk for tumour development in stem/progenitor cell compartments (Figure 1). REPLICATIVE EXHAUSTION AND DNA DAMAGE-INDUCED SENESCENCE The ‘replicative exhaustion’ that triggers senescence is essentially the erosion of telomeres. The telomeric regions found at the ends of chromosomes contribute to genomic stabilisation, and are shortened after each replication cycle. Once telomeres become critically short, they trigger senescence. Consistently, expression of telomerase, a reverse transcriptase that elongates telomeres, allows cells to proliferate beyond their normal replicative capacity and, accordingly, most cancer cells aberrantly express telomerase. The senescence phenotype can be induced in early passage cells by a variety of cellular stresses, including DNA damage, oncogenic stress, oxidative stress and suboptimal culture conditions. Telomere-associated replicative senescence is often considered to Cellular senescence and chromatin organisation M Narita 687 Table 1 Localisation and function of chromatin factors Proliferation Localisation and function General Senescence HPI H3 K9me3 MacroH2A HMGA1/2 Histone H1 Heterochromatin Heterochromatin Heterochromatin Chromatin architecture Linker histone SAHF component SAHF component SAHF component SAHF component Depleted H3 K9 acetyl H3 K4methyl Euchromatin Euchromatin Excluded from SAHF Excluded from SAHF HIRA Asf1a Histone chaperone Histone chaperone SAHF regulation SAHF regulation HMGA ¼ high-mobility group A; HP1 ¼ heterochromatin protein 1; SAHF ¼ senescence-associated heterochromatic foci. Pro-senescence activity Arbitrary Chromatin factors Mitogenic activity Time Mitogenic phase Senescence Figure 2 Oncogene-induced senescence (OIS). Constitutively active mitogenic stimuli induces rapid cell proliferation, but somehow the senescence machinery is triggered and eventually overcomes the mitogenic activity. Regeneration DNA damage-induced apoptosis and that generally senescent cells are resistant to apoptosis, cells appear to have the ability to cleverly handle cellular insults based on a fine-tuned balance between apoptosis and senescence. Differentiation Cancer? OIS Stre (...truncated)