The epigenetic regulator SIRT7 guards against mammalian cellular senescence induced by ribosomal DNA instability

Abstract

In the yeast , genomic instability in rDNA repeat sequences is an underlying cause of cell aging and is suppressed by the chromatin-silencing factor Sir2. In humans, rDNA instability is observed in cancers and premature aging syndromes, but its underlying mechanisms and functional consequences remain unclear. Here, we uncovered a pivotal role of sirtuin 7 (SIRT7), a mammalian Sir2 homolog, in guarding against rDNA instability and show that this function of SIRT7 protects against senescence in primary human cells. We found that, mechanistically, SIRT7 is required for association of SNF2H (also called SMARCA5, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A, member 5), a component of the nucleolar heterochromatin-silencing complex NoRC, with rDNA sequences. Defective rDNA-heterochromatin silencing in SIRT7-deficient cells unleashed rDNA instability, with excision and loss of rDNA gene copies, which in turn induced acute senescence. Mounting evidence indicates that accumulation of senescent cells significantly contributes to tissue dysfunction in aging-related pathologies. Our findings identify rDNA instability as a driver of mammalian cellular senescence and implicate SIRT7-dependent heterochromatin silencing in protecting against this process.

Inhibition of nucleolar stress response by Sirt1: A potential mechanism of acetylation‐independent regulation of p53 accumulation

“…Interestingly, a recent study has proposed a similar signaling model, in which Sirt1 regulates distribution and enzymatic activity of APE1 (apurinic/apyrimidinic endonuclease 1), a partner of NPM within the nucleolus (Lirussi et al, ). On the other hand, many studies have pointed to a critical role of Sirt7 in maintaining the normal structure and/or function of the nucleolus (Chenet al, ; Paredes et al, ). Interestingly, Sirt7 deficiency leads to nucleolar fragmentation and rDNA heterochromatin instability, and the nucleolar protective functions of Sirt7 in turn require a synergy with Sirt1 (Ianni, Hoelper, Krueger, Braun, & Bober, ).…”

DNA Break-Induced Epigenetic Drift as a Cause of Mammalian Aging

“…There is now abundant evidence that RCM occurs in higher organisms (Kane and Sinclair, 2019). Like Sir2 in yeast, three of the seven mammalian Sir2 homologs, SIRT1, SIRT6 and SIRT7, have dual roles as epigenetic regulators and facilitators of DNA break repair (Mao et al, 2011;Oberdoerffer et al, 2008;Paredes et al, 2018). Together, these histone deacetylases form repressive chromatin at telomeres, transposons, rDNA, and hundreds of genes involved in metabolism, circadian rhythms, inflammation, and DNA repair, among others (Kawahara et al, 2011;Oberdoerffer et al, 2008;Paredes et al, 2018;Simon et al, 2019;Van Meter et al, 2014) .…”

“…Like Sir2 in yeast, three of the seven mammalian Sir2 homologs, SIRT1, SIRT6 and SIRT7, have dual roles as epigenetic regulators and facilitators of DNA break repair (Mao et al, 2011;Oberdoerffer et al, 2008;Paredes et al, 2018). Together, these histone deacetylases form repressive chromatin at telomeres, transposons, rDNA, and hundreds of genes involved in metabolism, circadian rhythms, inflammation, and DNA repair, among others (Kawahara et al, 2011;Oberdoerffer et al, 2008;Paredes et al, 2018;Simon et al, 2019;Van Meter et al, 2014) . In response to an ATM-mediated DNA damage signal, RCM proteins relocalize to DSB sites to assist with repair by modifying histones and recruiting other DNA repair proteins (Dobbin et al, 2013;Mao et al, 2011;Oberdoerffer et al, 2008;Toiber et al, 2013).…”

A sirtuin's role in preventing senescence by protecting ribosomal DNA

“…SIRT7 was originally shown to increase transcription of rDNA loci, which is essential for cell viability in mammals (6). In the new study, Paredes et al (4) show that SIRT7 can have another, contrasting effect by interacting with SNF2H, a member of the ATP-dependent chromatin remodeling complex SWI/SNF, to specifically silence rDNA promoter regions ( Fig. 1).…”

“…In the current issue of JBC, Paredes et al (4) shed new light on the mechanisms underlying chromatin stability at rDNA loci by demonstrating that SIRT7-dependent heterochromatin silencing protects against cellular senescence. SIRT7 is a member of the mammalian sirtuin family of proteins, acting as a multifunctional chromatin regulator that influences transcription via deacetylation of histone H3K18ac (5) and whose function can be activated by dsDNA breaks.…”