SIRT1 Redistribution on Chromatin Promotes Genomic Stability but Alters Gene Expression during Aging

Abstract

Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin modifying proteins may be a conserved mechanism of aging in eukaryotes.

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

“…We examined the molecular mechanism of SIRT7 recruitment to DSBs. SIRT1 recruitment to damage sites is dependent on ATM activity (Oberdoerffer et al , 2008) and correlates with H4K16 hypoacetylation at DNA damage sites (O'Hagan et al , 2008). However, our results suggest that ATM activity is not required for the recruitment of SIRT7 to DSBs.…”

“…However, whether SIRT7 acquires novel functions under stress conditions remained unexplored. Similar to SIRT7, SIRT1 relocates from major satellite repeats to DNA damage sites with significant consequences for transcriptional regulation (Oberdoerffer et al , 2008). Indeed, SIRT1 is an apical effector involved in the stabilization of ATM at DNA breaks, which is essential for DDR propagation (Dobbin et al , 2013).…”

Epigenetic regulation of aging stem cells

“…In tissue-specific stem cells, SIRT1 may modulate chromatin state to coordinate stem cell responses to stress stimuli and DNA damage. Indeed, in murine embryonic stem cells, SIRT1 is important to maintain the genomic stability following DNA damage or oxidative stress (Oberdoerffer et al, 2008). Interestingly, a majority of SIRT1-bound genes that are deregulated in embryonic stem cells following oxidative damage also change with age in the adult neocortex, and the expression of these genes can be reverted upon Sirt1 overexpression in the mouse brain (Oberdoerffer et al, 2008).…”

“…Indeed, in murine embryonic stem cells, SIRT1 is important to maintain the genomic stability following DNA damage or oxidative stress (Oberdoerffer et al, 2008). Interestingly, a majority of SIRT1-bound genes that are deregulated in embryonic stem cells following oxidative damage also change with age in the adult neocortex, and the expression of these genes can be reverted upon Sirt1 overexpression in the mouse brain (Oberdoerffer et al, 2008). Taken together, these studies reveal a critical role for SIRT1 in mediating stem cell response to environment, a role that may become more crucial with age.…”

Sirt7 inhibits Sirt1-mediated activation of Suv39h1

“…Sirt1 exerts many effects that are beneficial for cellular survival such as improving metabolism, strengthening stress resistance and securing genome integrity [2,6–8]. In general, Sirt1 is believed to promote organismal health and delay aging.…”