SIRT7 slows down stem cell aging by preserving heterochromatin: a perspective on the new discovery
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Protein & Cell
HIGHLIGHT SIRT7 slows down stem cell aging by preserving heterochromatin: a perspective on the new discovery Luyang Sun, Weiwei Dang&
Stem cell aging is one of the leading theories of aging and is gaining momentum in recent years with the development of new technologies to study stem cells (Schultz & Sinclair, 2016). In the stem cell aging theory, the age-associated physiological changes and functional declines at tissue and organismal levels are attributed to changes to various stem cell populations, both in their quantity and function. Hence, one of the pressing questions in the aging research is to understand the molecular mechanisms that preserve stem cell function and delay their aging process. In this issue, Bi, et al., reports a novel mechanism that slows down the aging process in human mesenchymal stem cells by preserving the structure of heterochromatin, which is mediated through the functions of SIRT7, one of the seven sirtuins found in all mammals (Bi et al., 2020). Mammalian sirtuins are orthologs of yeast silent information regulator 2 (Sir2), an NAD+ dependent histone deacetylase that promotes genome stability and suppress the transcription at heterochromatin-like regions (Giblin et al., 2014). Since the first report on Sir2 that it extends budding yeast lifespan (Kaeberlein et al., 1999), great efforts have been made to explore the functions and mechanisms of sirtuins in aging and cellular senescence. The sirtuin family is evolutionarily conserved, from bacteria to mammals. Seven sirtuin members have been discovered in mammalian species, SIRT1-7. Although all of them contains a highly conserved NAD+- binding domain, their enzymatic activities, molecular functions, and cellular localizations vary greatly (Haigis & Sinclair, 2010). SIRT7 is the only sirtuin that predominantly located in nucleolus. Early studies reveal that it is a regulator of rDNA transcription (Ford et al., 2006; Grob et al., 2009), and protein synthesis (Tsai et al., 2014). To date, numerous studies greatly enrich our understanding of SIRT7 functions. SIRT7 is a versatile regulator that involved in a wide range of
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biological processes including but not limited to genome instability, apoptosis, stress response, heterochromatin maintenance, DNA damage repair, mitochondrion homeostasis, cellular senescence and aging (Blank & Grummt, 2017; Wu et al., 2018). Majority of the SIRT7 functions are mediated via its enzymatic activities, such as deacetylation of histone H3K18 (Barber et al., 2012) and several nonhistone proteins, and desuccinylation of H3K122 (Li et al., 2016), although Paredes et al. report that SIRT7 extends HSC lifespan by stabilizing SNF2H at rDNA promoters without its catalytic activity (Paredes et al., 2018). Consisted with its ortholog Sir2 in budding yeast, many lines of evidence showed that SIRT7 plays potent roles in cellular senescence and aging. SIRT7 deficient mice showed a shortened lifespan and aging related phenotypes (Vakhrusheva et al., 2008; Shin et al., 2013; Ryu et al.
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