Sirtuin 6 (SIRT6 or Sirt6) is a stress responsive protein deacetylase and mono-ADP ribosyltransferase

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

encoded by the SIRT6 gene. In laboratory research, SIRT6 appears to function in multiple molecular pathways related to aging, including

DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...

repair,

telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes (see #Sequences, Sequences). Telomeres are a widespread genetic feature most commonly found in eukaryotes. In ...

maintenance,

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...

and

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

. SIRT6 is member of the mammalian

sirtuin Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins ...

family of proteins, which are

homologs Homologous chromosomes or homologs are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during meiosis. Homologs have the same genes in the same loci, where they provide points along each chromosome th ...

to the yeast Sir2 protein.

Research

Sirt6 is mainly known as a deacetylase of

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...

s H3 and H4, an activity by which it changes chromatin density and regulates gene expression. The enzymatic activity of Sirt6, as well as of the other members of the sirtuins family, is dependent upon the binding of the cofactor

nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphat ...

(NAD+). Mice which have been genetically engineered to overexpress Sirt6 protein exhibit an extended

maximum lifespan Maximum life span (or, for humans, maximum reported age at death) is a measure of the maximum amount of time one or more members of a population have been observed to survive between birth and death. The term can also denote an estimate of the m ...

. This lifespan extension, of about 15–16 percent, is observed only in male mice.

DNA repair

SIRT6 is a

chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...

-associated protein that is required for normal

base excision repair Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...

and double-strand break repair of

DNA damage DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is constantly modified ...

in mammalian cells. Deficiency of SIRT6 in mice leads to abnormalities that overlap with aging-associated degenerative processes. SIRT6 promotes the repair of DNA double-strand breaks by the process of

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair ...

and

homologous recombination Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in Cell (biology), cellular organi ...

. SIRT6 stabilizes the repair protein

DNA-PKcs DNA-dependent protein kinase catalytic subunit, also known as DNA-PKcs, is an enzyme that plays a crucial role in repairing DNA double-strand breaks and has a number of other DNA housekeeping functions. In humans it is encoded by the gene designa ...

(DNA-dependent protein kinase catalytic subunit) at chromatin sites of damage. As normal human fibroblasts replicate and progress towards replicative senescence the capability to undergo homologous recombinational repair (HRR) declines. However, over-expression of SIRT6 in “middle-aged” and pre-senescent cells strongly stimulates HRR. This effect depends on the mono-ADP ribosylation activity of poly(ADP-ribose) polymerase ( PARP1). SIRT6 also rescues the decline in base excision repair of aged human fibroblasts in a PARP1 dependent manner.

Activators

Sirt6 deacetylation activity can be stimulated by high concentrations (several hundred micromolar) of fatty acids, and more potently by a first series of synthetic activators based on a pyrrolo

,2-a The comma is a punctuation mark that appears in several variants in different languages. Some typefaces render it as a small line, slightly curved or straight, but inclined from the vertical; others give it the appearance of a miniature fille ...

uinoxaline scaffold. Crystal structures of Sirt6/activator complexes show that the compounds exploit a SIRT6 specific pocket in the enzyme's substrate acyl binding channel. Among many

anthocyanidin Anthocyanidins are common plant pigments, the aglycones of anthocyanins. They are based on the flavylium cation, an oxonium ion, with various groups substituent, substituted for its hydrogen atoms. They generally change color from red through p ...

s studied,

cyanidin Cyanidin is a natural organic compound. It is a particular type of anthocyanidin (glycoside version called anthocyanin#Structure, anthocyanins). It is a pigment found in many red berries including grapes, bilberry, blackberry, blueberry, cherr ...

most potently stimulated activity of the SIRT6. SP-624 is also an activator of Sirt6.

References

External links

* * {{PDBe-KB2, Q8N6T7, NAD-dependent protein deacetylase sirtuin-6 Aging-related proteins