Sirt7 acts as a novel regulator of chromatin dynamics through modulation of the Sirt1/Suv39H1 axis: Possible role in cancer

Abstract

Sirtuins build a family of NAD+-dependent histone and protein deacetylases that are involved in a variety of cellular processes including proliferation, metabolism, genomic stability and stress response among others. Recently, it was discovered that one member of the sirtuin family, Sirt7, can regulate the activity of another sirtuin, Sirt1. Sirt7 inhibits Sirt1 catalytic activity by preventing its autodeacetylation at lysine 230. Through this mechanism, Sirt7 represses Sirt1-mediated inhibition of adipocyte differentiation and promotes accumulation of white adipose tissue. In this work, I unravel another layer of complexity in the crosstalk between Sirt7 and Sirt1. I demonstrate that Sirt7-mediated inhibition of Sirt1 plays a crucial role in the regulation of the catalytic activity of a prominent Sirt1 target: the methyltransferase, Suv39H1. Suv39H1 is an important histone modifier, which plays decisive role in the formation of constitutive heterochromatin mainly by catalyzing deposition of the histone mark H3K9me3. On the other hand, dissociation of Suv39H1 from constitutive heterochromatin is a critical event that ensures heterochromatin relaxation following genotoxic stress to implement DNA repair. Sirt1 promotes Suv39H1 activation through direct deacetylation. Here I demonstrate that Sirt7 indirectly inhibits Suv39H1 by restraining Sirt1 catalytic activity. In absence of Sirt7, Sirt1 is autodeacetylated and hyperactive and thus binds Suv39H1 with high efficiency. As a result, overactive Suv39H1 effectuates H3K9me3 deposition and leads to aberrant formation of constitutive heterochromatin in Sirt7 deficient cells. I further provide evidence that Sirt7-mediated inhibition of Sirt1/Suv39H1 axis is a crucial mechanism that establishes heterochromatin relaxation in response to stress. Cells lacking Sirt7 fail to reduce Suv39H1 recruitment to constitutive heterochromatin resulting in blunted heterochromatin relaxation following DNA damage, indicating an essential role of Sirt7 in DNA repair mechanism. Finally, I demonstrate that the Sirt7/Suv39H1 axis is involved in regulation of gene expression following genotoxic stress. My results suggest that Sirt7 controls the recruitment of Suv39H1 to euchromatin loci and ensures essential cellular responses to stress such as evasion from apoptosis and cell survival. Sirtuins possess a dual role in cancerogenesis based on their ability to act both as tumor suppressors mainly by facilitating DNA repair, or as oncogenes by stimulating cancer growth through different mechanisms. However, the exact mechanism underlying this duality still remains poorly characterized. My work reveals such a dual action of Sirt7. Since Sirt7 is upregulated in different types of cancer it might promote cancer progression by reducing Suv39H1 recruitment to the constitutive heterochromatin resulting in heterochromatin loss and genomic instability. Further, Sirt7 increases cell survival following DNA damage at least in part through Suv39H1. On the other hand, I show that Sirt7 possess potential tumor suppressor function by enforcing heterochromatin relaxation to allow DNA repair under stress. Although further work is required to better characterize the role of the Sirt7/Sirt1/Suv39H1 axis in cancer, my work suggests that the manipulation of this pathway may represent a novel alternative for the development of innovative anti-tumor therapies.