Sirt7 inhibits Sirt1-mediated activation of Suv39h1

Abstract

Sirtuins regulate a variety of cellular processes through protein deacetylation. The best-known member of mammalian sirtuin family, Sirt1, plays important roles in the maintenance of cellular homeostasis by regulating cell metabolism, differentiation and stress responses, among others. Sirt1 activity requires tight regulation to meet specific cellular requirements, which is achieved at different levels and by specific mechanisms. Recently, a regulatory loop between Sirt1 and another sirtuin, Sirt7, was identified. Sirt7 inhibits Sirt1 autodeacetylation at K230 and activation thereby preventing Sirt1-mediated repression of adipocyte differentiation by inhibition of the PPARγ gene. Here, we extend the regulatory complexity of Sirt7-dependent restriction of Sirt1 activity by demonstrating that Sirt7 reduces activation of a previously described prominent Sirt1 target, the histone methyltransferase Suv39h1. We show that removal of the acetyl-group at K230 in Sirt1 due to the absence of Sirt7 leads to hyperactivation of Sirt1 and thereby to constantly increased activity of Suv39h1.

Sirtuins and Insulin Resistance

“…In addition to Sirtuins, there are other epigenetic modification enzymes, including SUV39H1 and EZH2 are involved in insulin resistance and T2DM (271–276). There is an interaction between SUV39H1 and Sirtuins, including SIRT1, SIRT3, and SIRT7 (277–281). EZH2 is reportedly the deacetylating substrate of SIRT1 (282, 283).…”

Down‐regulation of Suv39h1 attenuates neointima formation after carotid artery injury in diabetic rats

“…Unfortunately, there was no significant difference in H3K9me3 levels in the promoter of complement C3, which indicated that direct histone methylation was not the main mechanism of Suv39h1’s effect on complement C3. Instead, one possible mechanism is that Suv39h1 depletion suppresses H3K9me3 in the promoter of peroxisome proliferator–activated receptor γ (PPARγ), leading to an increase in PPARγ expression, which then down‐regulates complement C3 levels indirectly …”

SIRT7 Acts as a Guardian of Cellular Integrity by Controlling Nucleolar and Extra-Nucleolar Functions

“…Genes 2021, 12, x FOR PEER REVIEW 2 of 14 activity of numerous histone modifiers such as methytransferases and acetyltransferases [8,9]. Notwithstanding, sirtuins control the activity and functions of enzymes, transcription factors, and other chromatin unrelated molecules mainly through direct deacetylation, highlighting their complex functions in the regulation of cellular processes [3].…”

“…The ability of sirtuins to control such a broad range of biological functions mainly derives from their capacity to control both chromatin-related and -unrelated targets. Sirtuins act as potent epigenetic silencers by promoting heterochromatin formation through the direct deacetylation of different histone marks or indirectly by controlling the activity of numerous histone modifiers such as methytransferases and acetyltransferases [ 8 , 9 ]. Notwithstanding, sirtuins control the activity and functions of enzymes, transcription factors, and other chromatin unrelated molecules mainly through direct deacetylation, highlighting their complex functions in the regulation of cellular processes [ 3 ].…”

“…Interestingly, cross-regulation between mammalian sirtuins is also employed to fine-tune their functions. The binding of SIRT7 to SIRT1 inhibits SIRT1 auto-catalytic activation resulting in the stimulation of adipogenesis and destabilization of constitutive heterochromatin [ 9 , 20 ]. In sharp contrast, binding of SIRT1 to SIRT7 is fundamental to promote the formation of ribosomal DNA heterochromatin and to repress E-cadherin expression, thus stimulating cancer metastasis [ 21 , 22 ].…”