Date Published: September 22, 2011
Publisher: Impact Journals LLC
Author(s): Michael Van Meter, Zhiyong Mao, Vera Gorbunova, Andrei Seluanov.
The sirtuin gene family comprises an evolutionarily ancient set of NAD+ dependent protein deacetylase and mono-ADP ribosyltransferase enzymes. Found in all domains of life, sirtuins regulate a diverse array of biological processes, including DNA repair, gene silencing, apoptosis and metabolism. Studies in multiple model organisms have indicated that sirtuins may also function to extend lifespan and attenuate age-related pathologies. To date, most of these studies have focused on the deacetylase activity of sirtuins, and relatively little is known about the other biochemical activity of sirtuins, mono-ADP ribosylation. We recently reported that the mammalian sirtuin, SIRT6, mono-ADP ribosylates PARP1 to promote DNA repair in response to oxidative stress. In this research perspective we review the role of SIRT6 in DNA repair and discuss the emerging implications for sirtuin directed mono-ADP ribosylation in aging and age-related diseases.
Sir2 enzymes, or sirtuins, are NAD+ dependent protein deacetylases and mono-ADP ribosyltransferases which regulate lifespan in S. cerevisiae , C. elegans  and D. melanogaster . In each of these systems, overexpression or hyperactivation of Sir2 or its homologs extends lifespan. In yeast, this lifespan extension is achieved by promoting genomic stability , regulating gene expression [5, 6] and suppressing the formation of extra-ribosomal circles [1, 7]. In the roundworm sir-2.1 promotes longevity by modulating daf-16 (FOXO) signaling  and regulating the proteostasis stress response ; Sir2 extends lifespan in the fruit fly by coordinating a different stress response – the dietary restriction pathway . Mammalian genomes encode seven Sir2 homologs (SIRT1-7); while it is unclear whether overexpression or hyperactivation of any of these sirtuins can extend lifespan, there is evidence that these genes can protect against several age-related pathologies, including neurodegeneration , hearing loss , diet induced obesity [11, 12] and cancer [13-15].