Page 12 - GPD-3-4

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

Through activation of glutamate dehydrogenase (GLUD), 2.6. SIRT6
SIRT3 promotes glucose formation from amino acids and Through its deacetylase and ADP-ribosyltransferase
suppresses glucose oxidation and glycolysis by indirectly activity, SIRT6 controls longevity and several essential
destabilizing the transcription factor hypoxia-inducible aging processes, including telomeric maintenance, gene
factor 1 alpha (HIF-1α). 25
expression, and DNA repair. In mammalian cells, SIRT6
2.4. SIRT4 is important for physiologically correct base excision
DNA repair (BER) and DNA double-strand break repair
SIRT4 is the only mitochondrial sirtuin with ADP- (DSBR) in the case of DNA damage. SIRT6 supports DNA
ribosyltransferase activity, and its overall catalytic repair through non-homologous end joining (NHEJ)
efficiency is up to 11-fold lower than the reported activity and homologous recombination. It plays a crucial role
33
of other sirtuins. It inhibits mitochondrial GLUD1 activity in maintaining cellular homeostasis, ensuring genome
and subsequently reduces insulin secretion. SIRT4 also stability, and regulating the inflammatory response. The
possesses low deacetylase, deacylase, and lipoamidase gene encoding SIRT6 is located on chromosome band
activities, through which it affects several metabolic 19p13.3. Unlike other sirtuins, SIRT6 and SIRT7 have
pathways, including ATP homeostasis, lipid oxidation, unique structures, as they lack a helix bundle at the NAD-
leucine catabolism, and insulin secretion. Like SIRT3, binding segment of the Rossmann fold, which connects the
SIRT4 is also highly expressed in mitochondria-rich catalytic domain to the zinc-binding domain. This distinct
tissues such as the heart, liver, spleen, kidneys, testes, structure of SIRT6, even in the absence of substrates,
ovaries, and prostate. The gene encoding SIRT4 is located underlies its strong affinity for binding to NAD. 34
on chromosome bands 12q24.23 – q24.31 and contains five
exons. 14 2.7. SIRT7
2.5. SIRT5 The main function of SIRT7 is to control ribosomal RNA
(rRNA) transcription. It also contributes to maintaining
In hepatic cells, SIRT5 regulates carbamoyl phosphate genomic stability and DNA repair, aids in the defense
synthetase 1, the enzyme catalyzing the ATP-dependent against oxidative stress, and promotes cell division in
reaction of carbamoyl phosphate synthesis from certain types of cells. The gene encoding SIRT7 is located
35
bicarbonate, ammonia, or glutamine, which is the first on chromosome band 17q25.3. SIRT7 is localized in the
step of the urea cycle in the mitochondria of liver cells. nucleolus, and it mainly interacts with RNA polymerase
29
The gene encoding SIRT5 is located on chromosome band (Pol) I and upstream binding factor. SIRT7 positively
6p23 and produces four protein isoforms: SIRT5iso1, regulates rRNA gene transcription and ribosome formation.
SIRT5iso2, and SIRT5iso3 (found in the mitochondria) Increased SIRT7 expression results in an increased rate
30
and SIRT5iso4 (found in the cytoplasm). SIRT5 is of RNA Pol I-mediated transcription, whereas decreased
expressed in all human tissues and organs, with the SIRT7 transcription has the opposite effect. The complete
highest levels in the heart, brain, liver, kidneys, testes, and absence of SIRT7 leads to the restriction of cell proliferation
muscle tissue. Although SIRT5 is mainly localized in the and the induction of apoptosis. Reduced SIRT7 levels also
mitochondrial matrix, it is also present in lower amounts lead to inefficient repair of DNA double-strand breaks
in the mitochondrial intermembrane space, peroxisomes, through the NHEJ mechanism. 36
nucleoplasm, and cytoplasm. SIRT5 has weak deacetylase
activity but exhibits strong demalonylase, desuccinylase, SIRT7 controls rRNA gene transcription through
and deglutarylase activities. In addition, SIRT5 is one interactions with RNA Pol I. By promoting the expression
of the regulators of several mitochondrial metabolism of rRNA genes, SIRT7 enhances ribosome biogenesis and
pathways, including fatty acid oxidation, amino acid protein synthesis, which can support the rapid proliferation
37
degradation, glycolysis, and, most importantly, ROS and of cancer cells. SIRT7 may influence the expression
31
cellular respiration regulation. SIRT5 also desuccinylates and activity of HIF-1α, a transcription factor involved
and activates GLUD1 and succinate dehydrogenase in cellular responses to hypoxia. HIF-1α regulates genes
(SDH), key enzymes in the TCA cycle and the electron associated with glycolysis, angiogenesis, and cell survival,
transport chain. Their activation supports the production and dysregulated HIF-1α signaling is implicated in cancer
of intermediates necessary for energy production and progression. 38
biosynthesis, potentially affecting the metabolic flexibility
of cancer cells. Enhanced SDH activity can lead to more 3. Role of sirtuins in cancer
efficient mitochondrial respiration and ATP production, Sirtuin dysregulation contributes to tumorigenesis by
impacting the energy metabolism of tumor cells. 32 altering key cellular processes, such as energy metabolism,
39

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