NAD-dependent deacetylase sirtuin 7 is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that in humans is encoded by the ''SIRT7''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
SIRT7 is member of the mammalian
sirtuin
Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins t ...
family of proteins, which are
homologs
A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci where they provide points alon ...
to the yeast Sir2 protein.
Function
SIRT7 facilitates the
transcription
Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including:
Genetics
* Transcription (biology), the copying of DNA into RNA, the fir ...
of DNA by
DNA polymerase I
DNA polymerase I (or Pol I) is an enzyme that participates in the process of prokaryotic DNA replication. Discovered by Arthur Kornberg in 1956, it was the first known DNA polymerase (and the first known of any kind of polymerase). It was initiall ...
,
DNA polymerase II
DNA polymerase II (also known as DNA Pol II or Pol II) is a prokaryotic DNA-Dependent DNA polymerase encoded by the PolB gene.
DNA Polymerase II is an 89.9-kDa protein and is a member of the B family of DNA polymerases. It was originally isolated ...
, and
DNA polymerase III
DNA polymerase III holoenzyme is the primary enzyme complex involved in prokaryotic DNA replication. It was discovered by Thomas Kornberg (son of Arthur Kornberg) and Malcolm Gefter in 1970. The complex has high processivity (i.e. the number of ...
.
In humans cells, SIRT7 has only been shown to interact with two other molecules:
RNA polymerase I
RNA polymerase 1 (also known as Pol I) is, in higher eukaryotes, the polymerase that only transcribes ribosomal RNA (but not 5S rRNA, which is synthesized by RNA polymerase III), a type of RNA that accounts for over 50% of the total RNA synthesiz ...
(RNA Pol I) and
upstream binding factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...
(UBF).
SIRT7 is localized to the nucleolus and interacts with RNA Pol I.
Chromatin immunoprecipitation Chromatin immunoprecipitation (ChIP) is a type of immunoprecipitation experimental technique used to investigate the interaction between proteins and DNA in the cell. It aims to determine whether specific proteins are associated with specific genom ...
studies demonstrate that SIRT7 localizes to rDNA, and
coimmunoprecipitation shows that SIRT7 binds RNA Pol I. In addition SIRT7 interacts with UBF, a major component of the RNA Pol I initiation complex.
It is not known whether or not SIRT7 is modifying RNA Pol I and/or UBF, and if so, what those modifications are.
SIRT7 is expressed more in metabolically active tissues, such as liver and spleen, and less in non-proliferating tissues, such as heart and brain.
Furthermore, it has been shown that SIRT7 is necessary for
rDNA transcription. Knock down of SIRT7 in
HEK293 cell
Human embryonic kidney 293 cells, also often referred to as HEK 293, HEK-293, 293 cells, or less precisely as HEK cells, are a specific immortalised cell line derived from a spontaneously miscarried or aborted fetus or human embryonic kidney cells ...
s resulted in decreased
rRNA
Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosoma ...
levels. This same study found that this SIRT3 knockdown decreased the amount of RNA Pol I associated with rDNA, suggesting that SIRT7 may be required for rDNA transcription. Knock down SIRT7 led to reduced RNA Pol I levels, but RNA Pol I mRNA levels did not change. This suggests that SIRT7 plays a crucial role in connecting the function of
chromatin remodeling
Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out ...
complexes to RNA Pol I machinery during transcription.
SIRT7 may help attenuate DNA damage and thereby promoting cellular survival under conditions of genomic stress.
Ribosomal DNA
Ribosomal DNA (rDNA) is a DNA sequence that codes for ribosomal RNA. These sequences regulate transcription initiation and amplification, and contain both transcribed and non-transcribed spacer segments.
In the human genome there are 5 chromos ...
(rDNA) is more vulnerable to DNA damage than DNA elsewhere in the
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
such than rDNA instability can lead to
cellular senescence
Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approxi ...
, and thus to
senescence-associated secretory phenotype
Senescence-associated secretory phenotype (SASP) is a phenotype associated with senescent cells wherein those cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases. SASP may also consist of exosom ...
.
SIRT7 localizes to rDNA thereby protecting against rDNA instability and cellular senescence.
DNA repair
Depletion of SIRT7 results in impaired repair of DNA double-strand breaks (DSBs) by the process of
non-homologous end joining
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...
(NHEJ).
DSBs are one of the most significant types of
DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
leading to genome instability. SIRT7 is recruited to DSBs where it specifically
deacylates histone H3
Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'beads on a stri ...
at lysine 18. This affects the focal accumulation of the DNA damage response factor
53BP1
Tumor suppressor p53-binding protein 1 also known as p53-binding protein 1 or 53BP1 is a protein that in humans is encoded by the ''TP53BP1'' gene.
Clinical significance
53BP1 is underexpressed in most cases of triple-negative breast cancer.
D ...
, a protein that promotes NHEJ by protecting DNA from end resection.
SIRT7
overexpression has been shown to improve efficiency of NHEJ by 1.5-fold, and of
homologous recombination
Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids (usually DNA as in cellular organisms but may ...
by 2.8-fold.
Accelerated aging
Sirt7 mutant mice show phenotypic and molecular features of
accelerated aging
Accelerated aging is testing that uses aggravated conditions of heat, humidity, oxygen, sunlight, vibration, etc. to speed up the normal aging processes of items. It is used to help determine the long-term effects of expected levels of stress wit ...
.
These features include premature curvature of the spine, reduced weight and fat content, compromised
hematopoietic stem cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
function and
leukopenia
Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...
, and multiple organ dysfunction.
Clinical relevance
This gene has been found to be involved in maintenance of
oncogenic transformation.
References
Further reading
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