Among the greatest challenges facing organisms is that of detecting and effectively responding to life-threatening environmental changes that are intimately associated with metabolic fluctuations and certain forms of stress. These conditions have been linked to the onset of many human pathologies, including cancer. Over the past decade, members of the Sir2 family, or sirtuins, have been described as major players in sensing and coordinating stress response. Evidence has imputed mammalian sirtuins in carcinogenesis, although the mechanisms involved seem to be more diverse and complex than previously anticipated. Some sirtuins, such as SirT2 and SirT6, seem to work as tumor suppressors, but others, such as SirT1, are apparently bifunctional: operating as both tumor suppressors and oncogenic factors depending on the context and the study conditions. The mechanisms underlying these apparently contradictory activities are not well understood, although recent findings suggest that they might actually be two sides of the same coin. In this review, the authors summarize current knowledge on the functional implications of sirtuins in cancer and discuss possible explanations for their functional duality.

The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G₂/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1–3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle.

The members of the Sir2 family, or sirtuins, are major regulators of the response to different types of stress. The members of the family have adapted to increasing complexities throughout evolution and have become diversified by increasing their number, specificity, and localization and acquiring novel functions. Sirtuins have been consistently implicated in the cross-talk between the genomic information and environment from the prokaryotes onward. Evidence suggests that in the transition to eukaryotes, histones became one of the basic and most conserved targets of the family, to the extent that in yeast and mammals, sirtuins were originally described as NAD⁺-dependent histone deacetylases and classified as class III histone deacetylases. A growing number of studies have determined that sirtuins also target a wide range of nonhistone proteins. Many of these targets are also directly or indirectly related to chromatin regulation. The number of targets has grown considerably in the last decade but has provoked an ill-founded discussion that neglects the importance of histones as sirtuin targets. In this review, we summarize our knowledge regarding the range of sirtuin targets described to date and discuss the different functional implications of histone and nonhistone targets throughout evolution.

Sirtuins are a family of deacetylases that target histone and non‐histone proteins and require NAD⁺ as an enzymatic cofactor for their enzymatic activity. This requirement confers sirtuins with the ability to detect changes in metabolism and energy homeostasis and to coordinate cellular responses to maintain genome integrity. Thus, sirtuins are crucial in the crosstalk between environment and genome, and therefore in responses to stress at the cell and organism levels. Sirtuins play a major role in maintaining genome integrity, largely through regulation of epigenetic mechanisms. They target different histone marks, including H4K16Ac, H3K9Ac, H3K56Ac and H3K18Ac, and non‐histone components of the chromatin machinery, such as enzymes and structural proteins. Here we summarize our current view on the link between sirtuins and epigenetics, one that reflects the continual adaptation of the genome to stress.

Since the earliest stages of evolution, organisms have faced the challenge of sensing and adapting to environmental changes for their survival under compromising conditions such as food depletion or stress. Implicit in these responses are mechanisms developed during evolution that include the targeting of chromatin to allow or prevent expression of fundamental genes and to protect genome integrity. Among the different approaches to study these mechanisms, the analysis of the response to a moderate reduction of energy intake, also known as calorie restriction (CR), has become one of the best sources of information regarding the factors and pathways involved in metabolic adaptation from lower to higher eukaryotes. Furthermore, responses to CR are involved in life span regulation—conserved from yeast to mammals—and therefore have garnered major research interest. Herein we review current knowledge of responses to CR at the molecular level and their functional link to chromatin.