Abstract
Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response.
Highlights
Aging is a physiological condition characterized by the functional deficit of tissues and organs due to the accumulation of senescent cells [1]
These include the shortening of the telomeres, the oncogene-induced replication stress, the oncogene-induced senescence (OIS), the accumulation of misfolded protein and/or oxidative stress [5]
The progressive accumulation of double-strand breaks (DSBs) at the chromosome ends is coupled with a deep epigenetic resetting that can be observed in pre-senescent cells, even distal from telomeres
Summary
Aging is a physiological condition characterized by the functional deficit of tissues and organs due to the accumulation of senescent cells [1]. Senescent cells are characterized by the permanent cell-cycle arrest sustained by the accumulation of cyclin-dependent kinase inhibitors/CDKi), like p16, p21 and p27, as well as by the release of cytokines, chemokines and soluble factors. This modified microenvironment is known as senescence-associated secretory phenotype (SASP) [4]. During senescence the epigenome undergoes temporal and sequential modifications that are mandatory to accomplish different cellular adaptations This epigenetic resetting is mainly due to the accumulation of irreparable DNA damage. The accumulation of irreparable DNA damage triggered during RS leads to permanent cell-cycle arrest and is considered among the main driving forces of aging [22]
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