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.

The Role of Nicotinamide in Cancer Chemoprevention and Therapy

“…Therefore, it is not easy to say if NAM inhibits or in fact stimulates SIRT1 in the long term and more preclinical research in this direction would be vital [38]. To make things more complicated, SIRT1 exhibits a dichotomous behavior and has been described as both tumor promoter and suppressor, while both SIRT1 up-regulation and down-regulation have been associated with cancer progression [45,[139][140][141][142]. Some studies have suggested that SIRT1 behavior is dependent on the oncogenic context [142].…”

“…SIRT1 and PARP1 carry out the protein posttranslational modifications called deacetylation and poly(ADP-ribosyl)ation (PARylation), respectively [38,39]. SIRT1 is a NAD + dependent class III histone deacetylase (HDAC) of histones and various non-histone transcription factors (e.g., p53) involved in diverse intracellular processes including DNA repair, metabolism, apoptosis, proliferation, hormone response, aging, and carcinogenesis [39,45,46]. Whereas NAD + stimulates SIRT1-mediated deacetylation of target proteins, low NAD + /NADH ratio diminishes SIRT1 activity [47].…”

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

“…[164][165][166][167] Similarly, DNA damage induces the relocalization of NAD + -dependent deacetylase SIRT1 to DNA breaks, which promotes DNA repair via opening the chromatin and recruiting the main DNA repair factors including KU70, NBS1, WRN, KAP1, XPA and APEX1. [168][169][170][171][172][173][174][175][176][177] Additionally, PARPs and sirtuins also simulate genomic damage-signaling kinases, including ATM, p53, DNA-PK, CIRBP and FOXOs, to accelerate DNA repair. [178][179][180][181][182] Given that DNA damage-activated PARPs account for up to 90% of cellular NAD + consumption, the DNA repair activity is highly dependent on the cellular NAD + concentration.…”

Conventional and unconventional interactions of the transcription factor FOXL2 uncovered by a proteome‐wide analysis

“…Interestingly, SIRT1 is known to regulate FOXL2 itself 22,23 and is a key player of DNA damage response, genome stability, stress response and senescence. 24 This bears a clear link with other partners such as XRCC6, also involved in DNA repair ( 21 and references therein). A recent proteomic analysis of tens of members of the Forkhead box (FOX) TF family using stably transfected human embryonic kidney cells 293 (HEK293) also pointed to many potential FOXL2 partners, 25 but did not study endogenous FOXL2.…”

“…18 It is also known that the interaction of FOXL2 with the DEAD-box protein 20 (DDX20) enhances FOXL2 pro-apoptotic function. 24 This bears a clear link with other partners such as XRCC6, also involved in DNA repair ( 21 and references therein). 6 To extend the known set of FOXL2-interacting proteins, we have previously performed a FOXL2 yeast-two-hybrid (Y2H) screening using an ovarian cDNA library.…”