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Κριτική της εργασίας |
“Epigenetic molecular genetics
in Multiple Myeloma”
Dr. Regkli
Areti, Konstadinedes Polidoros,
Mallis Panayiotis, Matsis Konstadinos, Constadinides Ioannis and Panagoula
Kollia.
Introduction
In most higher eucaryotic genomes,including
those of mammalian cells,approximately 5 percent of the C residues are modified
by methylation at the 5 position of the cytokine ring.Such methylations occur
almost exclusively at sequences to yield
mCpG (mC=5-methylcytosine) and appear symmetrically on both stands of the DNA
(since the CpG dinoucleotide is always base-paired with another CpG sequense in
the antiparallel double helix).Curiously,CpG sequences are themselves underrepresented
in genomes that contain mC ,being present at only about one-third the expected
frequency 1.
What
has become apparent in recent years is that certain CpG sites in the vicinity
of many genes are undermethylated in tissues where the gene is expressed,
compared to tissues where the gene is inactive.The use of particular
restriction enzyme pairs has provided a convenient and simple assay for
assessing the state of methylation of some subsets of CpG
sequences.Demethylation of active genes is not complete1,2.Up to 30
percent of the CpG sequences in transcribed regions are methylated,
compared to about 70 percent methylation of all
CpG sequences in animal cell DNA.As with Dnase sensitivity,undermethylation is
usually detected over a significantly larger region than the transcribed
portion of a particular gene and is often found in tissues where the gene is
not (yet) active but potentially activatable.1,2,3,4
Although
demethylation and expression are not coupled for every gene that has been
examined,in most cases the correspondence is quite striking.This prompt the
question of whether changes in DNA methylation are the cause or effect of gene
activation.Methylation could regulate
gene expression in two main ways.First,addition
of a 5-methyl group and proteins such as repressors and activators ,for the
5-methyl to cytosine could increage or decreage the interaction between the
specific DNA –protein recognition often takes
places.Second because DNA Group protrudes into the major groove of the double
helix where the addition of a 5-methyl group to C leads to molecular crowding
in the major groove,methylation tends to shift the conformational equilibrium
of the DNA away from the standard B-form toward other forms .Since DNA binding
proteins are generally sensitive to the configuration of the sugar –phosphate
backbone as well as to the base sequense at their
recognition sites,such conformational changes
could dramatically alter repressor (or avtivator ) binding .2,3Some
evidence that demethylation may indeed induce gene activation comes from
studies using 5-azacytidine (5 azaC),an analog of C.Strikingly ,5 –aza C
induces differentiation (turning on
the genes) in cultured mouse embryo
cells.Similarly in the case of a number of cloned genes that have been
reintroduced into mammalian cells the unmethylated form proves to be
more active than the deliberately methylated gene.However there are also
examples where demethylation lags behind gene expression.Thus the exact
relationship berween methylation and gene expression remains unclear,perhaps
because only a few of the potential methylation sites in DNA are critical for
gene control.Also nuclear is how selective demethylation of a critical site
might be accomplished when gene
activation is desired.A final puzzle arises from
the realization that some eucaryotic organisms regulate their genes perfectly
well without any DNA methylation
whatsoever1,2,3,4.
The epigenetic rhythm is determined by the
change which provokes the gene expression, and which the realization, with changes,
such as modification of histones, changes in methylation and acetylation of the
DNA.
Histone
Acetyltransferases-HATS
The acetylation of histones in
eykariotic organisms was discovered
quite a few years ago, and the identification as well as the characterization
of enzymes which create it have revealed their remarkable diversity in
different organisms.
Histone Acetyltransferases-HATS, is the name for
factors which allocate enzyme activation in the transportation of an
acetylation team from the acetyl-CoA to the e-amino of the group of amino-acids
lysine, that are usually found in the
basic region of N-terminal end of
histones. The total
number of enzymes-HATS are separed in
two categories:type A 19 found in the core and type B found in
cytoplasme 9,93. The HATS of type B are
considered to catalyse the acetylation of newly- composed proteins in the
cytoplasme , while the HATS of type A are considered that they participate in
the nuclear acetylation of the histone related with the transcription, as well.
The acetyltransferase of type B,
HAT1, was discovered in sacharomyces 57 and it acetylizes the lysin
5 and 12 of histone 4 (H4) in vitro,
amino-acids which were known to be found acetylated , in the newly synthesized
Η4 10. The
enzyme HAT1 constitutes a part of a multifactor complex whose subunits includes
also 14 proteins HAT2 and CAF1 which have been connected with the redevelopment
and the aggregation of the components of
the chromatin, respectively 82,55. Despite the particular significance attached
to HAT1, the transformation or HAT2 has not presented any problems in the
incorporation of H4 to the chromatin 82, which clearly indicates
that its action can be replaced by other enzymes when the HAT1 is absent or
cannot act.
Many of the proteins with HAT
activity can acetylized free
histones when used in vitro, while others such as the
nuclear ones, cannot acetylized their
physiologic substrate as they are but only when they are found in the whole
complex with other factors, that appear
that they are essential for their activity .
Another family of acetylates that has been found is the one of
MYST, which was named after and shaped by the strong resemblance they
bear with the concatenation of proteins MOZ, Ybf/Sas3, Sas2 and Tip60 22.
The Esa1 of Sacharomyces, the MOF
of Drosofilla and the human HBO1 and
MORF 76 constitute newer
members of family MYST which was discovered later.
The strong relationship between the
transcriptional activation and
acetylation of the histones was clearly
indicated when it was discovered that the larger subunit of the complex factors
that is connected with TVR (TVR Associated factors-TAFs), Taf1-taf250, allocates
the enzyme activity in the acetylation
of histones 73. The
complex TFIID can band to the DNA via the TVR factor that recognizes
special sequenses, athough it has been discovered that even TFIID that does not
carry TVR it can transcript in vitro .
The acetylotransferases
are involved in the transcriptional
regulation not only via the acetylation of histones but also by transcriptional factors 25.
Histone Deacetylases-HDACS
The acetylation of the histones is a
reversal procedure, as the acetyl group can be removed from the action of
special enzymes called apocetylase histones- (HDACS), the existence of which
was discovered shortly afterwards the presence acetylases 102 The deacetylase are categorized in families
and the enzymes of human class I, II and III are homologe to the ones of the
sacharomyces Rpd3, Hda2 and Sir2, respectively 103. Deacetylase hitones are
divided in units in which some of the subunits function and regulate the enzyme
activation. Apocetylase together with the histone acetylases contribute to the
acetylation of certain histones as well as the regulation and the
differentiation of different megafactors which are responsible for their
modification. The interaction between megafactors which advance to specific
alleles, has as a result their located action in instigators, which in turn
regulate the amount of quantity and the availability of the enzyme 4 63
Histone Methyltranferases-HMTs
The methylation histones is performed by
specific enzymes, the methylase histones, HMTs. Recently other enzymes that methylate the
histones in specific residues have been discovered and it has contributed in
the discovery of the transcription mechanism, as when the histones are
methylated show significant differences from the methylation known up to the
moment as post-translational.
The methylation of the histone does
not change the total charge of protein and it appears to be stable
modification, concurrently certain enzymes that remove methylgroup have been
discovered, but present special action 99,28,111. The methylation of
histones can be classified in two groups, those that methylate the lysine
residues18,100 and those methylated the
arginine residues, such as the family of PRMT. The amino-acid arginin can undergo only - or
di-methylation. The enzymes that end up in the
methylation Arginin residues are separated in two categories: Type I, which leads
to a single and asymmetrical di-methylation and Type II, which leads to a
single and symmetrtical di-methylation. There are five enzymes which involved in the
methylation reaction of arginin, and present high degree of maintainance of
catalytic region 18, that are
named prmt1-5. The methylation
histone is involved in the regulation of transcription mechanisms as much as in
the control of suppressive
activity on the transcription. The role of methylating histones during transcription is
characterized by an additional degree of complexity, the number methylated groups on a residue is
related to different attributes. 66 <>
The Methylation of the aminoacid lysine of histone
The
histone lysine that undergo methylation are the Lysine 4,.9,.27 and 36 and 79
on histone the 3 and lysine 20 on histone the
4. The enzymes that are involved in this the specific transformation
bring characteristic region SET, and the characteristic regions that are rich
in cytokines that precede, PRESET and follow, Post-set, respectively,to the
region where there is enzyme activity. The enzymes that methylated lysine of the histones can be
categorized in four large families: the SET1, which includes enzymes which methylate the K4
of H3, the SET2, which includes the enzymes which methylate the K36 of H3, the
RIZ and the family SUV39, which is consists of enzymes that can methylate the
K9 and K27 of H3 18
The
methylation the K79 of H3 is an exception since the enzyme that is responsible
for the modification, DOT1, does not brings the characteristic SET region 36.
The methylation of
K79 is related to the activity of the transcription and is considered
participate in preventing the spread Heterochromatosis. The first
methylated lysine which was discovered in from mammals and brings upon itself
an active methylated of K9 of H3 is Suv39h1, counterpart of Su (var) the 3-9
Drosofila 52
In certain cases where there is a later
expressive modification of factors from enzymes which modify the chromatin
during methylation of arginin or acetylase have been found and their fuction
appears in biological reactions, such as
translation 25,38 But for the enzymes from the methylated lysine
family with characteristic domain SET, the only known are the histones. Recently other enzymes
that methylate the K4 of H3, including the MLL, the ALL, hSET1 and hSMYD3 this 72,75,117,48
have been excluded from humans.
These proteins are usually part of mcromolecule structures, which include more
the one enzyme activity that modifiy the chromatin. In contrast with heterochromatin situation
which was mentioned, the potential role of the modification of the histone in
the consseration of the active translational chromatins has not being dified. If the modifications of
the histone press for some reaction to the controversial of the translational,
the methylation works as aactivation means for the gonads, because contrary to
the acetylation, the maethylation of the lysine is stable. In addition, sugnificant
levels of methylation of H3-K4 have been observed in the genes of region of
b-globulin and in the NF-4 during the cell diffentiation, before the
translation, showing that tis specific modification is involved in the
resolution and the conservation of one strong active chromatin 49,48
|
Ονομασία |
Τοποθεσία |
Μοριακή Λειτουργία |
|
p15 ή CDKN2B |
Chr9:21.99-22Mb |
•
Λειτουργία της κινάσης •
Πρόσδεση πρωτεϊνών •
Εξαρτώμενη από την κυκλίνη
πρωτεϊνική πρόσδεση κινάσης |
|
p16
ή CDKN2Α |
Chr9:21.96-21.98 Mb |
•
Πρόσδεση DNA •
Εξαρτώμενη από την κυκλίνη πρωτεϊνική
πρόσδεση κινάσης •
Πρωτεϊνική δραστηριότητα |
|
DAP |
Chr5:10.73-10.81
Mb |
•
Επαγωγή της απόπτωσης
με εξωκυτταρικά σήματα |
|
SOCS1 |
Chr16:11.26-11.26 Mb |
•
Δραστηριότητα πρωτεϊνικού υποδοχέα
κινάσης •
Πρόσδεση υποδοχέα αναπτυξιακού
παράγοντα ομοίου ινσουλίνης •
Πρόσδεση πρωτεϊνών |
|
BAX |
Chr19:54.15-54.16 Mb |
•
Πρόσδεση πρωτεϊνών •
Επικρατούσα περιοχή πρόσδεσης ΒΗ3 |
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