Sirtuin 6: linking longevity with genome and epigenome stability

Abstract

Sirtuin 6 (SIRT6) has been in the spotlight of aging research because progeroid phenotypes are associated with SIRT6 deficiency. SIRT6 has multiple molecular functions, including DNA repair and heterochromatin regulation, which position SIRT6 as a hub that regulates genome and epigenome stability. Genomic instability caused by persistent DNA damage and accumulating mutations, together with alterations in the epigenetic landscape and derepression of repetitive genetic elements, have emerged as mechanisms driving organismal aging. Enhanced levels of SIRT6 expression or activity provide avenues for rejuvenation strategies. This review focuses on the role of SIRT6 in the maintenance of genome and epigenome stability and its link to longevity. We propose a model where SIRT6 together with lamins control aging and rejuvenation by maintaining epigenetic silencing of repetitive elements.

Keywords: DNA damage repair; SIRT6; epigenome; healthspan; longevity; rejuvenation.

Figure 1.

SIRT6 structural domains. SIRT6 protein has a length of 355 amino acids (aa) and features three main structural domains: the N-terminus (1–24 aa), the catalytic core domain (25–268) and the C-terminus (269–355 aa). The catalytic core includes an NAD⁺-binding Rossmann fold domain spanning the regions of 25–132 aa and 195–268 aa, a histidine in position 133 serving as proton acceptor and a Zn²⁺ binding domain with several cysteine residues binding Zn²⁺ ion (positions 141, 144, 166, 177). Several well-known mutations in the catalytic core that impair SIRT6 functions are shown: substitution of a conserved histidine H133 to tyrosine leads to a complete loss of SIRT6 catalytic activity and impaired association with chromatin, S56Y mutation causes loss of both deacetylase and mono-ADP-ribosyltransferase activities, while G60A and R65A cause a lack of mono-ADP-ribosyltransferase activity and deacetylase activity respectively [47, 60]. The C-terminus is proline-rich and structurally disordered. It includes a nuclear localization signal (NLS) and a predicted nucleolar localization signal (NoLS). Several characterized phosphorylation sites are highlighted.

Figure 2.. SIRT6 at different stages of DNA repair.

Proper regulation of DNA repair is paramount for genomic stability, promoting longevity. SIRT6 is involved in the sensing of DSB through association with Ku80, 9–1-1 complex, APE1 and MYH glycosylase, as well as directly binding to DNA. Under oxidative stress (OS) SIRT6 can be phosphorylated by JNK at S10 and mono-ADP-ribosylates PARP1 at K521. PARP1 PARylates numerous proteins, promoting relaxation of chromatin. SIRT6 also promotes relaxation of chromatin via interactions with SNF2H, CHD4, GCN5 and KDM2A, which increases accessibility of the damage site for the DNA repair machinery. SIRT6 participates in DNA damage response (DDR) signaling through the regulation of DNA-PKcs, and formation of γ-H2AX foci. Furthermore, SIRT6 can interact with SUV39H1, potentially playing a role in chromatin restoration after repair.

Figure 3.. SIRT6 and epigenome maintenance.

Changes in heterochromatin and de-repression of repetitive sequences pose danger for both genomic and epigenomic stability. SIRT6 deacetylates H3K9 and H3K56, TRF2, increases association of WRN with chromatin and interacts with SUV39H to promote telomere stability. SIRT6 deficiency results in telomere dysfunction, susceptibility of oxidative stress (OS) and may lead to the expression of the telomere proximal genes (TPG). At the centromeres SIRT6 deacetylates H3K18 to maintain silencing of centromeric satellite repeats and interacts and promotes proper chromosome segregation during mitosis, with the defect observed in the absence of SIRT6. SIRT6 is involved in silencing of retrotransposable elements: SIRT6 mono-ADP-ribosylates KAP1, associated with HP1α, to keep a closed conformation of chromatin at LINE1 elements, preventing retrotransposon expression. The lack of SIRT6 results in de-repression of LINE1 elements, produces genomic instability and innate immune response through accumulation of LINE1 cDNA copies and activation of cGAS-STING-IFN type I pathway.

Figure 4.. Packaging of retrotransposable elements into heterochromatin controls aging and rejuvenation.

Embryonic stem cells (ESC) and induced pluripotent cells (iPSCs) lack lamin A. Retrotransposons are open and expressed. Upon differentiation SIRT6 facilitates packaging of retrotransposons into silent lamin A-bound chromatin. During aging heterochromatin unravels, retrotransposons become expressed and drive inflammation, while SIRT6 binds to shortened telomeres and damaged DNA and becomes limiting. SIRT6 overexpression can rejuvenate chromatin structure without changing cell fate.