The role of SIRT1 and SIRT6 in epigenetic regulation of genome stability under stress

Abstract

The Sirtuin family of NAD+-dependent enzymes plays a key role in the maintenance of genome integrity upon stress. Sirtuins coordinate the response to different forms of stress at different levels and have been involved in a wide range of processes directly linked to tumorigenesis such as genome stability, cell cycle regulation, apoptosis, senescence and DNA repair. The main objective of this work was to deepen the role of Sirtuins in genome stability and cancer. This has been fulfilled through the development of two specific objectives: First, to define the factors that contribute to the role of SIRT6 in tumorigenesis. Second, to decipher the role of SIRT1 in DNA damage signaling and repair. SIRT6 is an important regulator of genome stability and metabolic homeostasis and has been shown to work as a tumor suppressor. This antitumoral activity is directly associated to the epigenetic silencing of a specific set of genes involved in glucose metabolism, but little is known about the partners of SIRT6 in this functional context. Previous studies of the group identified two histone H3K9 specific histone methyltransferases (HMTs) Suv39h1 and G9a, as interaction partners of SIRT6. Both Suv39h1 and G9a are responsible for methylation of H3K9, a hallmark of heterochromatin organization, transcriptional repression, and epigenetic silencing. Several studies have shown correlation of altered expression of Suv39h1 and G9a in cancer. In the first specific objective of the thesis, we studied the functional relationship between SIRT6 and Suv39h1 as well G9a to provide evidence about the mechanism behind the described tumor suppressor activity of SIRT6. Our results support a direct Sirtuins have been also implicated in the regulation of the DNA damage response (DDR) signaling, and DNA repair, being SIRT1 is the best studied Sirtuin in this functional context. In the second specific objective, we studied the role of SIRT1 in DNA damage signaling. SIRT1-deficient cells show impairment of the DDR, which result in an increased genome instability and decreased levels of yH2AX.