Chromatin regulation and genome maintenance by mammalian SIRT6

Abstract

Saccharomyces cerevisiae Sir2 is an NAD(+)-dependent histone deacetylase that links chromatin silencing to genomic stability, cellular metabolism and lifespan regulation. In mice, deficiency for the Sir2 family member SIRT6 leads to genomic instability, metabolic defects and degenerative pathologies associated with aging. Until recently, SIRT6 was an orphan enzyme whose catalytic activity and substrates were unclear. However, new mechanistic insights have come from the discovery that SIRT6 is a highly substrate-specific histone deacetylase that promotes proper chromatin function in several physiologic contexts, including telomere and genome stabilization, gene expression and DNA repair. By maintaining both the integrity and the expression of the mammalian genome, SIRT6 thus serves several roles that parallel Sir2 function. In this article, we review recent advances in understanding the mechanisms of SIRT6 action and their implications for human biology and disease.

Figure 1

From yeast to mammals: Parallel functions for Sir2 and SIRT6. A) Schematic of yeast Sir2 and mammalian SIRT6, highlighting the conserved central sirtuin domain (blue). B) Overlapping functions for Sir2 and SIRT6 in regulating telomeric chromatin, genomic stability, and gene expression. i. At yeast telomeres, histone deacetylation by Sir2 is required for telomere position effect, the reversible silencing of sub-telomeric gene expression. SIRT6 is required for generating a proper chromatin structure at human telomeres; this structure allows the binding of the telomere-processing factor WRN and prevents aberrant telomere metabolism. Whether SIRT6 is important for gene silencing due to telomere position effect in human cells is not currently known. ii. Yeast Sir2 maintains genomic stability by preventing recombination at the rDNA locus, thus suppressing formation of senescence-inducing extrachromosomal rDNA circles (ERCs). In mammalian cells, SIRT6 contributes to genomic stability by preventing chromosomal fusions between dysfunctional telomeres, by enabling efficient DNA repair, and perhaps by regulating H3K56 acetylation. iii. Sir2 is required for the transcriptional silencing of three heterchromatin-like domains in yeast: inactive mating-type loci, sub-telomeric DNA, and rDNA repeats. Although SIRT6 also represses gene expression, its reported effects thus far are at euchromatic regions of the genome (NF-κB and HIF1α target genes).

Figure 2

Chromatin-bound: SIRT6 regulates multiple chromatin-templated processes. A. SIRT6 deacetylates H3K9 and H3K56 at telomeres, and SIRT6 depletion triggers aberrant telomere metabolism. B. SIRT6 enables efficient DSB repair. C. Although the role of SIRT6 in BER has not been clearly defined, the spectrum of DNA damage sensitivities of Sirt6^−/− mouse cells and the results of functional complementation assays suggest a potential chromatin-regulatory function for SIRT6 in this repair pathway. D. SIRT6 represses NF-κB and HIF1α target gene expression, and might act in conjunction with other transcription factors (TFs) to regulate additional gene expression programs. Question marks indicate hypothesized or uncharacterized roles for SIRT6.

Figure 3

From orphan enzyme to site-specific deacetylase. By deacetylating lysines 9 and 56 on histone H3, SIRT6 modulates chromatin structure to regulate telomere integrity, DNA repair, and gene expression, thus impacting on processes important for cancer, metabolism, and aging.