The Epigenetics Revolution полностью

Most histone deacetylases are very promiscuous. By this we mean they will deacetylate any acetylated histone they can find. Indeed, as mentioned above, many don’t even restrict themselves to histones, and will take acetyl groups off all sorts of proteins. However, SIRT6 isn’t like this. It only takes the acetyl groups off two specific amino acids – lysine 9 and lysine 56, both on histone H3. The enzyme also seems to have a preference for histones that are positioned at telomeres. When Katrin Chua knocked out the SIRT6 gene in human cells, she found that the telomeres of these cells got damaged, and the chromosomes began to join up. The cells lost the ability to divide any further and pretty much shut down most of their activities[246].

This suggested that human cells need SIRT6 so that they can maintain the healthy structures of telomeres. But this wasn’t the only role of the SIRT6 protein. Acetylation of histone 3 at amino acid 9 is associated with gene expression. When SIRT6 removes this modification, this amino acid can be methylated by other enzymes present in the cell. Methylation at this position on the histone is associated with gene repression. Katrin Chua performed further experiments which confirmed that changing the expression levels of SIRT6 changed the expression of specific genes.

SIRT6 is targeted to specific genes by forming a complex with a particular protein. Once it’s present at those genes, SIRT6 takes part in a feedback loop that keeps driving down expression of the gene, in a classic vicious cycle. When the SIRT6 gene is knocked out, the levels of histone acetylation at these genes stays high because the feedback loop can’t be switched on. This drives up expression of these target genes in the SIRT6 knockout mice. The target genes are ones which promote auto-destruction, or the cell’s entry into a state of permanent stasis known as senescence. This effect explains why SIRT6 knockdown is associated with premature ageing[247]. It’s because genes that accelerate processes associated with ageing are switched on too soon, or too vigorously, at a young age.

It’s a little like a crafty manufacturer installing an inbuilt obsolescence mechanism into a product. Normally, the mechanism doesn’t kick in for a certain number of years, because if the obsolescence activates too early, the manufacturer will get a reputation for prematurely shoddy goods and nobody will buy them at all. Knocking out SIRT6 in cells is a little like a software glitch that activates the inbuilt obsolescence pathway after, say, one month instead of two years.

Other SIRT6 target genes are associated with provoking inflammatory and immune responses. This is also relevant to ageing, because some conditions that become much more common as we age are a result of increased activation of these pathways. These include certain aspects of cardiovascular disease and chronic conditions such as rheumatoid arthritis.

There is a rare genetic disease called Werner’s syndrome. Patients with this disorder age faster and at an earlier age than healthy individuals. The condition is caused by mutations in a gene that is involved in the three-dimensional structure of DNA, keeping it in the correct conformation and wound up to the right degree of tightness for a specific cell type[248]. The normal protein binds to telomeres. It binds most effectively when the histones at the telomeres have lost the acetyl group at amino acid 9 on histone H3. This is the precise modification removed by the SIRT6 enzyme. This further strengthens the case for a role of SIRT6 in control of ageing[249].

Given that SIRT6 is a histone deacetylase, it might be interesting to test the effect of a histone deacetylase inhibitor on ageing. We would predict that it would have the same effects as knocking down expression of the SIRT6 enzyme, i.e. it would accelerate ageing. This might give us pause for thought when we plan to treat patients with histone deacetylase inhibitors such as SAHA. After all, an anti-cancer drug that makes you age faster isn’t that attractive an idea.

Fortunately, from the point of view of treating cancer patients, SIRT6 belongs to a special class of histone deacetylase enzymes called sirtuins. Unlike the enzymes we met in Chapter 11, the sirtuins aren’t affected by SAHA or any of the other histone deacetylase inhibitor drugs.

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