The Role of SIRT1 on DNA Damage Response and Epigenetic Alterations in Cancer

Abstract

Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC), an NAD+-dependent enzyme deeply involved in gene regulation, genome stability maintenance, apoptosis, autophagy, senescence, proliferation, aging, and tumorigenesis. It also has a key role in the epigenetic regulation of tissue homeostasis and many diseases by deacetylating both histone and non-histone targets. Different studies have shown ambiguous implications of SIRT1 as both a tumor suppressor and tumor promoter. However, this contradictory role seems to be determined by the cell type and SIRT1 localization. SIRT1 upregulation has already been demonstrated in some cancer cells, such as acute myeloid leukemia (AML) and primary colon, prostate, melanoma, and non-melanoma skin cancers, while SIRT1 downregulation was described in breast cancer and hepatic cell carcinomas. Even though new functions of SIRT1 have been characterized, the underlying mechanisms that define its precise role on DNA damage and repair and their contribution to cancer development remains underexplored. Here, we discuss the recent findings on the interplay among SIRT1, oxidative stress, and DNA repair machinery and its impact on normal and cancer cells.

Keywords: DNA damage/repair; SIRT1; cancer development; epigenetics.

Figure 1

SIRT1 as an epigenetic regulator and DNA repair response modulator. SIRT1 contributes to heterochromatin formation and can be associated with transcriptionally repressed repetitive DNA loci (1); upon stress, SIRT1 can be dissociated from these regions towards the DNA damage site, resulting in chromatin reorganization which favors transcriptional changes (2); SIRT1 recruits epigenetic machinery to the transcriptional silencing around the DNA damage site (3); SIRT1 also participates in the recruitment and deacetylation of DDR (4) and DNA repair proteins, (5) helping in many steps of repair pathways.