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Gene & Protein in Disease Human sirtuins (SIRT1-7) in cancer

selected genetic targets, which allows sirtuins to influence protein structure of sirtuins consists of an evolutionarily
various cellular processes, such as stress resistance and conserved central catalytic core (containing ~275 amino
energy conservation during low-calorie situations, acids), composed of two interconnected subdomains: a
2+
cell survival, transcription, DNA repair, apoptosis, Rossmann-fold subdomain and a Zn -binding variable
inflammation, tissue regeneration, neuronal signaling, module. The conserved central domain is the designated
and circadian rhythm. During caloric restriction, the area for NAD binding and is responsible for the catalytic
3,4
tricarboxylic acid (TCA) cycle slows down due to reduced activity of sirtuins. The binding cleft for the nicotinamide
glucose and free fatty acid intake by cells. The conversion and ribose parts of NAD and the acetyllysine substrate is
of NAD to reduced nicotinamide adenine dinucleotide formed by connected loops of subdomains of the central
(NADH) is coupled with TCA cycle reactions. Therefore, domain. Substrate binding and catalysis are mediated
8
calorie restriction can raise the mitochondrial NAD/ by invariant amino acids situated in the binding cleft.
NADH ratio, whereas a high-calorie diet can lower it. As a Variations in the binding cleft’s hydrophobicity and charge
sirtuin cosubstrate, an increase in the NAD concentration distribution enable distinct human sirtuins to exhibit
is enough to increase sirtuin activity in cells, which can act varying levels of substrate selectivity. Despite different
as stress adaptors. 5 substrate selectivity, the homologous catalytic core allows
catalysis through the same deacylation mechanism in all
The first sirtuin ever discovered was found in the yeast 2
Saccharomyces cerevisiae and named Sir2. Humans have human sirtuins.
6
seven sirtuin isoforms homologous to yeast Sir2. SIRT1 2. Characterization of sirtuins in normal cell
– 7 differ in target structures, enzymatic activity, and physiology
subcellular localization (Table 1). The diversity of target
structures is possibly attributed to N- and C-terminal 2.1. SIRT1
extensions with varying sequences and lengths, which As one of the epigenetic regulators, SIRT1 is involved in the
contribute to specificity in the localization and regulation DNA damage response, acting as a histone deacetylase at
of different types of human sirtuins. Different cellular the site of damage and an activator of DNA repair proteins.
localizations of sirtuins have a predisposing effect on their Histone acetylation and deacetylation are two primary
function. SIRT1 and 2 can be localized in the cytoplasm or epigenetic regulatory mechanisms, and modifications
nucleus, depending on the current cell cycle phase. SIRT6 is in histones and chromatin availability as a response to
localized in the nucleus and SIRT7 in the nucleolus. Nuclear environmental factors or DNA damage can affect gene
sirtuins target and interact mainly with histones and expression and regulate DNA repair. Yeast Sir proteins
transcription factors. SIRT3 – 5 is mitochondrial sirtuins, can repress gene transcription by modifying chromatin
mainly affecting mitochondrial processes. The primary into its functionally inactive form, heterochromatin, by
7
polymerizing across nucleosomes. Alterations in acetylation
and methylation leading to genomic instability are currently
recognized as the key features of aberrant cell proliferation
and carcinogenesis. SIRT1 was the first mammalian
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sirtuin discovered and is thus the most extensively studied
sirtuin. SIRT1 shares the highest homology with Sir2, and
the gene encoding SIRT1 is located on chromosome band
10q21.3 and contains nine exons and eight introns. SIRT1
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can be localized either in the cytoplasm or nucleus, and it
is characterized by deacetylation activity, regulating fatty
acid oxidation, glucose metabolism, chromatin structure,
the cell cycle, and insulin secretion. Considering the
impact of SIRT1 on several biological processes (e.g., cell
senescence, apoptosis, oxidative stress, and inflammation),
even minor changes in its expression and function can
significantly affect these events. The expression of SIRT1
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and the deacetylase activity of SIRT1 protein are regulated
by tumor protein p53, hypermethylated in cancer 1, testis-
Figure 1. Subcellular localization of mammalian sirtuins. Adapted from
Haigis and Sinclair. 3 specific protein Y-encoded-like 2, checkpoint kinase 2, and
Abbreviation: SIRT: Silent information regulator. cell cycle and apoptosis regulator 2. 9

Volume 3 Issue 4 (2024) 2 doi: 10.36922/gpd.4100