MикроРНК: от фундаментальных исследований до их приложения
МикроРНК – малые, некодирующие белок РНК длиной 20–30 нуклеотидов. В клетках эукариотов микроРНК выполняют роль биорегуляторов экспрессии генов через механизм ингибирования или модуляции процесса трансляции. Цель обзора – проанализировать механизмы биогенеза и функционирования микроРНК, стратегию их...
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Ширина, Т.В. Бобровская, М.Т. Козлов, Э.А. 2019-06-20T04:15:01Z 2019-06-20T04:15:01Z 2007 MикроРНК: от фундаментальных исследований до их приложения / Т.В. Ширина, М.Т. Бобровская, Э.А. Козлов // Біополімери і клітина. — 2007. — Т. 23, № 6. — С. 467-482. — Бібліогр.: 228 назв. — рос., англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000781 https://nasplib.isofts.kiev.ua/handle/123456789/157501 577.21:615.01:616-092 МикроРНК – малые, некодирующие белок РНК длиной 20–30 нуклеотидов. В клетках эукариотов микроРНК выполняют роль биорегуляторов экспрессии генов через механизм ингибирования или модуляции процесса трансляции. Цель обзора – проанализировать механизмы биогенеза и функционирования микроРНК, стратегию их открытия, предоставить краткий перечень биологических процессов, в регуляции которых принимают участие микроРНК, а также ознакомить с новейшими публикациями, посвященными причастности микроРНК к различным патологиям (особенно канцерогенезу) и использованию их для маркирования, диагностики, профилактики и терапии раковых болезней человека. MicroRNAs (miRs) are small non-protein-encoding RNAs of 20–30 nucleotides long. In eukaryotic cells miRs play the role of bioregulators of gene expression through the mechanisms of translation repression/modulation. Here we both familiarize the readers with miRs biogenesis, functioning mechanisms, and strategy of their discovery and present the list of biological processes, regulated by miRs. We also list the publications, dedicated to miRs role in human pathologies (carcinogenesis in particular) and their application for marking, prevention, diagnostics, and therapy of cancer. МікроРНК – короткі некодуючі РНК довжиною 20–30 нуклеотидів. У клітинах еукаріотів мікроРНК відіграють роль біорегуляторів експресії генів, пригнічуючи або модулюючи процес трансляції. Мета огляду – проаналізувати механізми біогенезу та функціонування мікроРНК, стратегію їхнього відкриття, надати перелік деяких біологічних процесів, у регуляції яких беруть участь мікроРНК, а також ознайомити з новітніми публікаціями, присвяченими причетності мікроРНК до різних патологій (особливо канцерогенезу) і застосуванню їх для маркування, профілактики, діагностики та терапії різних хвороб. ru Інститут молекулярної біології і генетики НАН України Біополімери і клітина Огляди MикроРНК: от фундаментальных исследований до их приложения МікроРНК: від фундаментальних досліджень до практичного застосування MicroRNA: from fundamental research to their application Article published earlier |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine |
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DSpace DC |
| title |
MикроРНК: от фундаментальных исследований до их приложения |
| spellingShingle |
MикроРНК: от фундаментальных исследований до их приложения Ширина, Т.В. Бобровская, М.Т. Козлов, Э.А. Огляди |
| title_short |
MикроРНК: от фундаментальных исследований до их приложения |
| title_full |
MикроРНК: от фундаментальных исследований до их приложения |
| title_fullStr |
MикроРНК: от фундаментальных исследований до их приложения |
| title_full_unstemmed |
MикроРНК: от фундаментальных исследований до их приложения |
| title_sort |
mикрорнк: от фундаментальных исследований до их приложения |
| author |
Ширина, Т.В. Бобровская, М.Т. Козлов, Э.А. |
| author_facet |
Ширина, Т.В. Бобровская, М.Т. Козлов, Э.А. |
| topic |
Огляди |
| topic_facet |
Огляди |
| publishDate |
2007 |
| language |
Russian |
| container_title |
Біополімери і клітина |
| publisher |
Інститут молекулярної біології і генетики НАН України |
| format |
Article |
| title_alt |
МікроРНК: від фундаментальних досліджень до практичного застосування MicroRNA: from fundamental research to their application |
| description |
МикроРНК – малые, некодирующие белок РНК длиной 20–30 нуклеотидов. В клетках эукариотов микроРНК выполняют роль биорегуляторов экспрессии генов через механизм ингибирования или модуляции процесса трансляции. Цель обзора – проанализировать механизмы биогенеза и функционирования микроРНК, стратегию их открытия, предоставить краткий перечень биологических процессов, в регуляции которых принимают участие микроРНК, а также ознакомить с новейшими публикациями, посвященными причастности микроРНК к различным патологиям (особенно канцерогенезу) и использованию их для маркирования, диагностики, профилактики и терапии раковых болезней человека.
MicroRNAs (miRs) are small non-protein-encoding RNAs of 20–30 nucleotides long. In eukaryotic cells miRs play the role of bioregulators of gene expression through the mechanisms of translation repression/modulation. Here we both familiarize the readers with miRs biogenesis, functioning mechanisms, and strategy of their discovery and present the list of biological processes, regulated by miRs. We also list the publications, dedicated to miRs role in human pathologies (carcinogenesis in particular) and their application for marking, prevention, diagnostics, and therapy of cancer.
МікроРНК – короткі некодуючі РНК довжиною 20–30 нуклеотидів. У клітинах еукаріотів мікроРНК відіграють роль біорегуляторів експресії генів, пригнічуючи або модулюючи процес трансляції. Мета огляду – проаналізувати механізми біогенезу та функціонування мікроРНК, стратегію їхнього відкриття, надати перелік деяких біологічних процесів, у регуляції яких беруть участь мікроРНК, а також ознайомити з новітніми публікаціями, присвяченими причетності мікроРНК до різних патологій (особливо канцерогенезу) і застосуванню їх для маркування, профілактики, діагностики та терапії різних хвороб.
|
| issn |
0233-7657 |
| url |
https://nasplib.isofts.kiev.ua/handle/123456789/157501 |
| citation_txt |
MикроРНК: от фундаментальных исследований до их приложения / Т.В. Ширина, М.Т. Бобровская, Э.А. Козлов // Біополімери і клітина. — 2007. — Т. 23, № 6. — С. 467-482. — Бібліогр.: 228 назв. — рос., англ. |
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REVIEWS
MicroRNA: from fun da men tal re search to their
ap pli ca tion
T. V. Shirina, M. T. Bobrovskaya, E. A. Kozlov
Institute of molecular biology and genetics NAS of Ukraine
Academicain Zabolotnog str., 150, Kyiv, 03680 Ukraine
E.mail: kozlov@imbig. org. ua
MicroRNAs (miRs) are small non-pro tein-en cod ing RNAs of 20-30 nu cleo tides long. In eukaryotic cells
miRs play the role of bioregulators of gene ex pres sion through the mech a nisms of trans la tion re pres -
sion/mod u la tion. Here we both fa mil iar ize the read ers with miRs biogenesis, func tion ing mech a nisms, and
strat egy of their dis cov ery and pres ent the list of bi o log i cal pro cesses, reg u lated by miRs. We also list the
pub li ca tions, ded i cated to miRs role in hu man pa thol o gies (carcinogenesis in par tic u lar) and their ap pli ca -
tion for mark ing, pre ven tion, di ag nos tics, and ther apy of can cer.
Key words: microRNA, biogenesis, ex pres sion pro file, bioinformatic, microRNA-pre dic tion, bioregulation,
carcinogenesis, ther apy.
In tro duc tion. The be gin ning of the cen tury was re -
nowned for one of the great est dis cov er ies, which
could be com pared with the dis cov ery of dou ble
stranded DNA by James Wat son and Fran cis Crick or
with the dis cov ery of re verse tran scrip tion by Howard
Temin and Da vid Bal ti more. This dis cov ery can be
con sid ered to be the rev o lu tion ary one as it not only
sup ple ments our ideas on growth reg u la tion and dif fer -
en ti a tion of cells and wid ens the ideas on var i ous cell
me tab o lism and the pro cesses of de vel op ment of the
or gan ism but also helps to per ceive the par a digm of
med i cal treat ment of var i ous dis eases, es pe cially can -
cer dis eases and dis eases of de vel op ment, based on the
afore men tioned knowl edge. This is the dis cov ery of
mi nor RNA mol e cules, ca pa ble of in duc ing RNA-in -
ter fer ence.
Two groups of mi nor in ter fer ing RNA. The two
groups dif fer in biogenesis and in the role they play in
or gan isms, yet have many com mon fea tures in the
mech a nisms of their func tion ing. The class of mi nor
RNAs is rep re sented by small non-cod ing RNAs
(snRNAs), 20–30 nu cleo tides long. Func tion ing of
snRNA re sults in si lenc ing of gene ex pres sion at
transcriptional and post-transcriptional lev els due to
com ple men tary in ter ac tions as a part of
ribonucleoprotein (RNP) effector com plexes with their
DNA- (level of tran scrip tion) and RNA- (level of trans -
la tion) tar gets [1]. In this pa per we de scribe only the
sec ond (from the point of view of chro nol ogy of dis -
cov ery) group of snRNAs, i.e. microRNAs, miRNAs,
or miRs.
How ever, prior to dis cuss ing miRs we need to men -
tion the first group of snRNAs – small in ter fer ing RNA
or siRNAs. This group is rep re sented by dou -
ble-stranded spi ral RNA, 22 and 28–30 nu cleo tides
long which are due to oc cur af ter split ting of large dou -
ble-stranded RNA by RNAase III endonuclease, also
known as Dicer [2, 3]. Ac cord ing to the source of dou -
467
ISSN 0233-7657. Biopolymers and cell. 2007. vol. 23. N 6. Translated from Ukrainian.
Ó T. V. SHIRINA, M. T. BOBROVSKAYA, E. A. KOZLOV, 2007
ble-stranded RNA in the cell, siRNAs can be clas si fied
into two sub-groups, which are spe cific for dif fer ent bi -
o log i cal ef fect and dif fer ent func tions. Un like dou -
ble-stranded RNA, which are de liv ered into the cell by
vi ruses and transgenes or oc cur af ter ab er rant syn the sis
of RNA, “diced” siRNAs of 22 nu cleo tides long func -
tion as the mech a nism of cell pro tec tion from non-spe -
cific allogenic RNA, and pres ent a sort of im mune re -
sponse at the level of RNA [2]. If dou ble-stranded
RNA is syn the sised in the cell in the nat u ral way from
ge nome re gion, which in cludes centromeres,
transposons, telomeres or re peats, “diced” siRNAs of
28–30 nu cleo tides long take an ac tive part in the
epigenetic pro cesses, re sult ing in si lenc ing of genes at
the level of tran scrip tion [4].
That is about all we wanted to men tion in re gard to
the first group of snRNAs – siRNAs – to em pha size the
prin ci pal dif fer ences from the sec ond group of small in -
ter fer ing RNA – miRs.
Dif fer ent as pects of ge nome or gani sa tion,
biogenesis, reg u la tion of tran scrip tion, func tion ing of
miRNAs and their role in the reg u la tion of dif fer en ti a -
tion and cell growth, as well as the de vel op ment of or -
gan ism and var i ous cell pro cesses are the sub ject of re -
views [5–7]. Hence, the aim of cur rent re view is to turn
the at ten tion of mo lec u lar bi ol o gists onto these tiny
bioregulators, which, ap par ently, take part in all cell
pro cesses.
Dis tri bu tion and lo cal isa tion of miRs genes. The
prin ci pal dif fer ence of miRs is their endogenic or i gin,
i.e. cell genomes con tain miR genes. The lat ter were
dis cov ered in al most all rep re sen ta tives of eukaryotes
and in large DNA-con tain ing vi ruses (ex cept for
RNA-con tain ing hu man im mu no de fi ciency vi rus
(HIV)) [8], ge nome of which is in cor po rated into the
host ge nome. Usu ally miR genes are lo cal ized in the
intergenic re gion of en cod ing chains as sin gle genes or
their clus ters [9]. They are lo cated in the intron re gions
of en cod ing genes (intronic miRs) [10, 11] and in
transposon el e ments [12].
miRs biogenesis. There is hardly any in for ma tion
on the ini ti a tion and reg u la tion of tran scrip tion of pri -
mary tran script (pri-miR) for miR as well as on the fac -
tors, reg u lat ing ex pres sion of miRs. Reg u la tion of
miR-155 ex pres sion was shown in Bur kitt’s lym phoma
to take place at two lev els: i) level of tran scrip tion, in -
volv ing proteinkinase C and nu clear kappa B fac tor and
ii) level of pro cess ing via yet un dis cov ered mech a nism
[13].
Lee et al. [14] iden ti fied nu mer ous reg u la tory el e -
ments, lo cated in 5¢-po si tions to wards miRs genes,
known to be sig nif i cant for transcriptional and
post-transcriptional reg u la tion of ex pres sion of miRs.
Fukao et al. [15] re vealed that miRs are pre dom i nantly
con trolled by unique cis-reg u la tory el e ments, which
co-de velop with miRs se quences. These data re veal the
pos si ble par tic i pa tion of well-char ac ter ized tran scrip -
tion fac tors, pro tein-en cod ing genes, in the ex pres sion
of miRs genes. miRs along with tran scrip tion fac tors
make the reg u la tory net work ing, con trol ling thou sands
of genes, pos si bly in clud ing ex pres sion of miRs genes
[16]. The lat ter were shown to be co-ex pressed with
their mRNA-tar gets. At the same time mammalians
were dem on strated to have two classes of cy clic ex pres -
sion co-reg u la tion of miRs and their tar gets with pos i -
tive and neg a tive feed back [17], which in volves miRs
as sta bi liz ing and destabilizing fac tors in the dy nam ics
of the gene ex pres sion [18]. Ap par ently,
transcriptional reg u la tion of miRs gene ex pres sion is
con trolled via some epigenetic mech a nisms [19–21].
The mech a nisms, based on sin gle nu cle o tide poly mor -
phism [22–24] and A®I-ed it ing of the pre de ces sors
and ma ture miRs [25–29] can be pos si bly in cluded to
the list of mech a nisms of post-translational reg u la tion
of ex pres sion of miRs genes.
In case if miRs genes are lo cated within the
intergenic re gion, pri-miRs are tran scribed with
RNA-poly mer ase II [30, 31], at the same time, if they
are lo cal ized in introns, then the pro duc tion of pri-miR
is also sup ple mented by the mech a nism of RNA splic -
ing [10, 11]. In some cases miRs are tran scribed by
RNA-poly mer ase III. Thus, au thors of [32] dem on -
strated that the clus ter of miRs genes, lo cated among
Alu-re peats on hu man chro mo some 19, is tran scribed
by RNA-poly mer ase III but not RNA-poly mer ase II.
It re mains un known whether it is a unique case or a
rule for miRs genes, lo cated in ge nome re gions, tran -
scribed by RNA-poly mer ase III. Au thors in [33] de ter -
mined the ma jor ity of the in ves ti gated miRs genes of
nem a tode, hu man, and two plant spe cies to pos sess the
same type of pro moter spe cific for pro tein-en cod ing
genes (TATA). How ever, a sig nif i cant num ber of
468
SHIRINA T. V., BOBROVSKAYA M. T., KOZLOV E. A.
genes are of in def i nite type. The au thors de vel oped a
new method of fore see ing the pro mot ers, re mind ing
cis-act ing el e ments, for tran scrip tion ini ti a tion. The
value and the sec ond ary struc ture of tran scribed
pri-miRs may vary sig nif i cantly [31]. Length-wise
they may be from 100 to sev eral thou sand nu cleo tides
long. There are cases of pri-miRs, spe cific for
poly-A-se quences and cap struc ture, i.e. ca pa ble of per -
form ing func tions of mRNA [34]. The spec i fic ity of
sec ond ary struc ture of pri-miRs is the pres ence of
hair-loop struc ture – hair pins – re gard less of their
length [35]. In some cases, they may con tain 1–2 hair -
pins [36] or sev eral as in the case of clus ter lo cal iza tion
of pri-miR genes [9, 37, 38].
The next stage of miR biogenesis is the split ting of
pri-miR in the nu cleus by RNAase III, also called
Drosha [35]. Scheme of miR biogenesis is pre sented in
Fig.1. Drosha chips off the hair pin out of pri-miR –
miR pre cur sor, pre-miR. Cer tain rules have to be
abided re gard ing the struc ture of pre-miR hair pin as a
part of pri-miR for suc cess ful chip ping off by Drosha.
Split takes place be tween sev eral (1–5) non-paired
bases, then hair pin stem, con tain ing not less than 10
b.p., is split. Hair pin stem may in clude non-paired
bases as well. The most suc cess ful split ting oc curs at
the pres ence of branchy non-paired chains at the hair pin
base. Chip ping off takes place at the base and cap tures
1–2 nu cleo tides of the hair pin stem. The length of
pre-miR may usu ally vary (»50–80 nu cleo tides). Hair -
pins may in clude non-paired bases of both arms (5¢ and
3¢), form ing sym met ri cal loop, and of one arm only –
asym met ri cal loops (up to 10 b.p.). Yet ex cep tions may
oc cur. The pres ence of pri-miR hair pins in plants is not
con sid ered to be the rule. pre-miR hair pins, if they are
pro cessed, vary sig nif i cantly in length (from 60 up to
300 nu cleo tides) and in shape [39, 40]; e.g.
pre-miR-169, 196 nu cleo tides long, con tains one asym -
met ri cal loop, 44 nu cleo tides long, in each of the stem
arms [39]. In most of the cases, ma ture miRs are
chipped off dou ble-stranded ex tended pri-miR re gions,
which do not nec es sar ily form hair-pin loop struc ture
[40]. Later on we will dis cuss some pos si ble rea sons of
such ex cep tions.
Drosha en zyme is known to func tion in the hu man
body with RNA-bind ing pro tein, called Pa sha or
DGCR-8 [41] (Fig.1). In this tan dem Pa sha acts as
pri-miR bind ing pro tein, while Drosha pro vides
nucleolytic ac tiv ity of the com plex. Pa sha pro tein con -
sists of 773 amino acid res i dues and con tains N-ter mi -
nal do main (1–275), re spon si ble for nu clear lo cal iza -
tion, two do mains in C-ter mi nal re gion, re spon si ble for
pri-miR bind ing and one do main (692–750) is re spon si -
ble for bind ing with Drosha [41]. Au thors of [42] sug -
gested the model of rec og ni tion of pri-miR by DGCR-8
pro tein on crys tal lo graphic struc ture of core re gion of
429–720. Crys tal lo graphic struc ture of C-ter mi nal do -
main of Dicer, re spon si ble for pro duc tion of miRs, was
stud ied by Takeshita et al. [43]. Drosha in mice is rep -
re sented by a com plex of two sub units, one of which is
DEAD-con tain ing helicase sub unit which rec og nizes
pri-miR [44].
The next stage of miR biogenesis is ex port of
pre-miR hair pins, chipped off pri-miR, from the nu -
cleus to cy to plasm [45–47] (Fig.1), car ried out with the
par tic i pa tion of pro tein translocation fac tor Exportin 5.
In cy to plasm pre-miR in ter acts with Dicer
endonuclease, which cuts dou ble stranded in ter me di ate
prod uct miR/miR*, 20–25 nu cleo tides long, out of the
hair pin. This prod uct ini ti ates the for ma tion of effector
RNA-in duced com plex, re sult ing in si lenc ing of genes,
i.e. RISC – RNA in duced si lenc ing com plex, the main
pro tein com po nents of which are Dicer, helicase,
RNA-bind ing pro tein, and argonaute-pro tein, re spon si -
ble for the for ma tion of RISC [5–7, 48–52]. In
Drosophila Dicer-pro cess ing en zyme as a part of
RISC-com plex func tions in tan dem with RNA-bind ing
pro tein Loqs, which re sults in the for ma tion of
intramolecular dimer [48]. Au thors de scribe “func -
tional anat omy” of Dcr-1/Loqs-com plex and de tails of
pre-miR split ting mech a nism.
Helicase is known not only to un twist
miR/miR*-du plex but also to be a sig nif i cant com po -
nent of miR me tab o lism. Along with other com po -
nents, helicase takes part in “load ing” of RISC-com -
plex [49].
Plants are spe cific for a dif fer ent mech a nism of
split ting. They pos sess four Dicer-like en zymes [50].
In Arabidopsis, DCL-1 pro tein and two other pro teins
HYL-1 and SE form an intramolecular com plex, which
is in cluded into SmD3/SmB-body, lo cal ized in the nu -
cleus [51]. The au thors put for ward a sup po si tion that
DCL-1/HYL-1/SE-com plex is in volved into miR pro -
469
MicroRNA: FROM FUN DA MEN TAL RE SEARCH TO THEIR AP PLI CA TION
duc tion in the nu clear SmD3/SmB-bod ies. These data
are con firmed by re sults in [52]. Dic ing (D)-bod ies, as
de fined by the au thors of [52], take part in “sym phonic”
pro cess ing of pri-miR–pre-miR–miR in nu clei of plant
cells. The facts men tioned (the ex is tence of four
DCL-en zymes, nu clear lo cal iza tion of D-bod ies) al low
sup pos ing that plants are spe cific for the ab sence of in -
ter me di ate prod uct of miR-me tab o lism – pre-miR – and
the above men tioned ab nor mal hair pins are the dis cov -
ered pri-miRs.
Helicase in RISC-com plex or in D-bod ies un twists
miR/miR*, pas sen ger miR* chain is elim i nated, and
RISC re mains with com ple men tary chain of 20–25 nu -
cleo tides long, i.e. ma ture miR. Ma ture miR may be
pro cessed from ei ther 5¢- or 3¢-arm of pre-miR, or from
both arms. The lat ter fact is sup posed to de pend on
ther mo dy namic sta bil ity of 5¢- or 3¢-arms of pre-miR.
The cells usu ally choose the least sta ble miR and de -
stroy the other one. Nev er the less, Ro et al. [53] dem on -
strated that in some tis sues both chains may be ac cu mu -
lated as paired miRs un til they are not sub jected to the
se lec tion in other tis sues. Both miRs are ca pa ble of
sup press ing ex pres sion of their genes in such tis sues.
Mam ma lian miRs may be im ported back to the nu cleus
in some cases.
Thus, au thors of [54] re vealed that spe cific miRs
some times con tain ad di tional hexanucleotide el e ment
in 5¢-ter mi nal se quence, which de ter mines their
subcellular lo cal iza tion. The same au thors dem on -
strated that hav ing joined miR-296, the men tioned ter -
mi nal mo tif con trols its nu clear im port. The ac cu mu la -
tion of ma ture miR in the nu cleus was also shown in
[55], where the au thors de fined that rat miR-206 is as -
so ci ated with form ing ri bo somes, as well as with 28S
rRNAs of func tion ing ri bo somes in cy to plasm. This is
a short re view of the mech a nism of miR gene ex pres -
sion. We may also sup pose that plant miRs, formed in
the nu cleus, are ex ported into cy to plasm.
Mech a nism of miRs func tion ing. How does the ma -
ture miR func tion? The model of miR func tion ing is
pre sented in Fig.2. Hav ing re mained in RISC-com plex
miR be comes a “guide” for miRISC-com plex. It guides
effector RNP-com plex to the tar get, which is pre sented
by mRNA and where ma ture miR finds its com ple men -
tary re gion. Due to miR complementarity with
RNA-tar get the com plex is re tained on mRNA, in hib it -
ing the pro cess of trans la tion [45, 46]. Long et al. [56]
re vealed the in flu ence of sec ond ary struc ture of
mRNA-tar get on rec og ni tion of its miRs. They also
sup posed the ex is tence of two-step re ac tion of hy brid -
iza tion of miR and mRNA. A®I-ed it ing of miRs and
their tar gets in flu ences the rep er toire of mRNA-tar gets
for miRs and re dis tri bu tion of tar gets [26–29]. The
mech a nism of in hi bi tion is of two sides and is known to
de pend on the de gree of miR complementarity to its tar -
get. If miR is com ple men tary in its 5¢- and 3¢-terminal
se quences, 5–7 nu cleo tides long, and is not com ple -
men tary in the cen ter (5–7 nu cleo tides), form ing a
ledge, then the com plex is placed on 3¢-un trans lated re -
gion (3¢ UTR) of mRNA. In this case the pro cess of
trans la tion is in hib ited. The se lec tion of tar gets is in flu -
enced by some specificities of 3¢ UTR [57–59]. It was
shown that suc cess ful in hi bi tion is achieved with 5¢
miR end, while 3¢-end vari abil ity is pos si ble [60–62].
There may be sev eral bind ing cen ters on 3¢ UTR. For
in stance, mRNA lin-14, en cod ing nu clear pro tein, nec -
es sary for tran si tion of Caenorhabditis elegans larva
470
SHIRINA T. V., BOBROVSKAYA M. T., KOZLOV E. A.
Fig. 1. Scheme of miR biogenesis. See text for de tails.
from age 1 to age 2, is known to con tain seven bind ing
cen ters with miR-lin4 [63]. The in ves ti ga tion of the
mech a nisms of in hi bi tion has been com menced only re -
cently [64] and it is far from giv ing clear re sults. There
are sev eral mech a nisms, dif fer ent in fine de tails of mo -
lec u lar in ter ac tion of RNA and pro tein com po nents –
the par tic i pants of this com pli cated pro cess [47, 65].
We will not take time to de scribe the de tails but will
name only some stages of this pro cess. Re pres sion is
known to re quire cap-struc ture and poly-A-se quence
[66-69], and to oc cur af ter trans la tion ini ti a tion [70].
Ev i dent is the fact that bind ing of miRISC with
mRNA-tar get takes place in poly somes. Thus, ex po -
nen tially grow ing HeLa cells showed the ma jor ity of
three miRs to be as so ci ated with ac tively trans lated
mRNA, while hu man miR-let7a blocks pro tein syn the -
sis on ac tively trans lat ing lin-41 mRNA poly somes, as -
sist ing in ac cu mu la tion of grow ing polypeptides [71,
72]. Poly somes were pre cip i tated in saccharose con -
cen tra tion gra di ent to gether with miR-let-7a and
Ago-pro tein. Sup pos edly, miRISC blocks pro tein syn -
the sis, con trib ut ing to fast de scent of ri bo somes with
grow ing polypeptide chains dur ing trans la tion elon ga -
tion [47, 65]. The des tiny of the lat ter re mains un cer -
tain, yet some sup po si tions are pre sented in [47, 65].
Later on it has been de ter mined that in hib ited mRNA
along with miRISC is as so ci ated with P-bod ies (Fig.2)
[45–47]. The au thors of [73] showed that re al iza tion of
mRNA out of poly somes is in suf fi cient for the ini ti a -
tion of P-bod ies as sem bly – re leased mRNA should
take part in in hi bi tion of me tab o lism, ini ti ated by miR.
The au thors made the con clu sion that P-bod ies are not
oblig a tory for func tion ing, but are the con se quences of
me tab o lism of si lenc ing of genes with the par tic i pa tion
of miR. P-bod ies con tain high con cen tra tions of en -
zymes and fac tors, nec es sary for re pres sion of trans la -
tion or mRNA turn over. In this sit u a tion two vari ants
are pos si ble: i) miRISC in ter acts with decapping pro -
teins and trans la tion ini ti a tion fac tor 4E, at the same
time as sist ing in the in hi bi tion and split ting of mRNA;
ii) mRNA in ter acts with helicase pro tein p54,
oligomerisation of com plex p54–mRNA takes place
and mRNA is pre served till better times. When nec es -
sary, this pre served mRNA may en ter the trans la tion
cy cle again [45, 74]. How ever, it re mains un known
how the cell se lects the way of re al iza tion. Be sides, this
scheme was de ter mined for miR-let7, which is com -
monly known to split mRNA-tar gets, re gard less of its
in com plete complementarity (poly-A-se quence is
chipped off) [47, 65, 75].
This is the first supposable mech a nism of in hi bi tion
of trans la tion with miR, which is based on in com plete
complementarity of miR and mRNA tar get, as a part of
miRISC-effector com plex, which en gages miR “guid -
ing” role, and effector pro tein p54 de ter mines whether
RNA should be split or pre served for fur ther re peated
trans la tion [45].
The sec ond mech a nism of in hi bi tion of miR trans -
la tion in plants is the cut ting of mRNA-tar get ac cord ing
to siRNA mech a nism [39, 76, 77]. Sim i lar mech a nism
was shown on one of miRs of BART2 of Ep stein-Barr
vi rus (EBV) [78]; it is per formed in the cases when miR
is com pletely com ple men tary to its tar get. The split ting
takes place via the cen ters of com ple men tary re gions. It
is ob vi ous that the se lec tion of mech a nism of in hi bi tion
de pends on the complementarity of the cen tral re gion of
471
MicroRNA: FROM FUN DA MEN TAL RE SEARCH TO THEIR AP PLI CA TION
Fig. 2. The model of miR func tion ing. See text for de tails.
miR ~7 nu cleo tides long. In ter est ingly, in some cases
the split ting, ini ti ated by miR, re sults in the for ma tion
of siRNA out of mRNA split ting prod ucts [40, 76, 77].
Some times 5¢-prod uct of mRNA split ting does not
synthesize siRNA. Some sci en tists be lieve that these
unsplit 5¢-prod ucts may be func tion ally nec es sary for
plants. It is sup posed that split ting of mRNA, re sult ing
in siRNA for ma tion, takes place out side of P-bod ies.
The data of the type and place of miR split ting are
rather con tro ver sial. There are some works that claim
that split ting in some points takes place in endonuclease
con tain ing P-bod ies [79]. How ever, it con tra dicts the
data, ob tained on miR-166 in Arabidopsis, the tar get for
which is mRNA of PHV gene [77]. This work dem on -
strates that miR-166, com pletely com ple men tary to its
tar get, as sists in split ting of mRNA, 656 nu cleo tides
long, and the ac cu mu la tion of 5¢-ter mi nal prod uct of
split ting, 500 nu cleo tides long. Dicer of RISC-com -
plex, ini ti ated by miR-166, acts as mul ti ple-use en -
zyme, as one com plex splits ~30 tar get mol e cules. This
mech a nism is un likely to be the same if the com plete
split ting took place in P-bod ies with endonuclease as -
sis tance. It is the most likely that the split in one point
takes place in P-bod ies ac cord ing to the sec ond type,
with the ac cu mu la tion of 5¢-half of mRNA, as it has
been shown for let-7 [45].
Up to this mo ment we re viewed the works, prov ing
down-reg u la tion of trans la tion in case of miR bind ing
to 3¢-UTR mRNA (mam mals, in ver te brates) or to the
en cod ing mRNA re gion (plants). How ever, miRs may
also up-reg u late mRNA, mod u lat ing the pro cess of
trans la tion [80–82]. miRs can mod u late bind ing cen -
ters for pro teins, in ter act ing with mRNA [80, 82]. It is
sup posed that bind ing of one or more miR to mRNA
may re sult in conformational changes in mRNA, and
con se quently, to re veal ing or mask ing of ad di tional
reg u la tory el e ments on mRNA. This may oc cur in case
of lo ca tion of miR bind ing cen tres within 5¢-non-cod -
ing re gion of mRNA-tar get. Up-reg u la tion of ex pres -
sion of hep a ti tis vi rus type C was dem on strated dur ing
the in ter ac tion of miR-122, spe cific for host liver, with
5¢-re gion of vi ral RNA [81]. Two miRs, interacting
with 5¢-re gion of their mRNA-tar gets, were dis cov ered
in plants (Arabidopsis) [83]. Ev i dently, mod u la tion of
trans la tion pro cess is per formed when miR is bound to
3¢-UTR mRNA and is ac cu mu lated in P-bod ies for re -
cur rent trans la tion, which was de monstrated for hu man
let-7 miR [45].
On the ba sis of re vealed mech a nism of miR func -
tion ing a def i nite con clu sion can be made that bi o log i -
cal ef fect of miR de pends on pro teins, en coded in their
mRNA-tar gets, as well as on the pro cesses these pro -
teins par tic i pate in. But be fore pro ceed ing to that we
need to men tion the meth ods of dis cov ery and iden ti fi -
ca tion of miR.
The strat egy of dis cov ery and in ves ti ga tion of miRs.
As of to day some strat e gies of dis cov er ing and in ves ti -
gat ing in di vid ual miR have al ready been de vel oped,
and some are still be ing elab o rated, mainly in clud ing
two ba sic ap proaches, namely bio chem i cal and
bioinformatical [84, 85]. Bio chem i cal ap proach uses
to tal RNA, ex tracted from tis sues, di vided by ei ther
gel-fil tra tion or elec tro pho re sis in 15% polyacrylamide
gel, con tain ing so dium dodecyl sul fate and 7M urea, in
or der to iso late and to iden tify miR. The zone of
low-mo lec u lar RNA (20–30 nu cleo tides) is mod i fied
and am pli fied with sub se quent clon ing and se quenc ing.
The meth ods de vel oped al low iden ti fy ing miRs, dif fer -
ent in one nu cle o tide, in 25 pmoles [86]. Thus, this is
the way in di vid ual miRs are iso lated and num bered.
Be sides, there is one work on iso lat ing a spe cific
15S-com plex of miR from RNP, con tain ing 40 in di -
vid ual miRs, from HeLa cells [87]. Some meth ods de -
vel oped are aimed at the iden ti fi ca tion of miRS ex -
pres sion pro files [88, 89], i.e. iden ti fi ca tion of time of
ap pear ance, syn the sis, and elim i na tion of miRs in the
or gans and tis sues dur ing carcinogenesis. Wang et al.
[88] de vel oped ac cu rate and sen si tive method of miRs
pro fil ing, which al lows dis crim i nat ing RNA in the cell
de gree- and se quence-wise and de ter min ing in di vid -
ual miRs in tis sues, held by for ma lin and cov ered with
par af fin. Work [90] can be an ex am ple of de scrip tion
of ex pres sion pro files of 23 miRs in carcinogenesis of
Drosophila at the em bry onic stages, and lar vae of
three dif fer ent age groups i.e. prepupal, pu pal, and
adult fe male. This work dem on strates that some miRs
are syn the sized con sti tu tively dur ing carcinogenesis
(miR-1, miR-8), oth ers at the stage of em bryo only
(miR-2, miR-3), and some – miR-34 – at the stage of
larva, and are syn the sized in ten sively in adult spec i -
men, whereas miR-125 and let-7 – only at the stages of
pupa.
472
SHIRINA T. V., BOBROVSKAYA M. T., KOZLOV E. A.
Let us have a look at the bioinformatical ap proach
to in ves ti ga tion of miRs. Com puter pro grams are be -
ing de vel oped to pre dict the pres ence of hair pin-loop
struc tures (pre-miR) and ma ture miRs as parts of these
hair pins [91–94], as well as the pres ence of mRNA tar -
gets for miR [61, 85, 95–102]. The pre dic tion of
pre-miR and ma ture miR hair pins is based on one cri -
te rion: can di dates for pre-miR should pos sess spe cific
sec ond ary struc ture of hair pin-loop shape, 60–100 nu -
cleo tides long, with sev eral sym met ri cal or asym met -
ri cal “bub bles” (sev eral un paired bases). Mfold com -
puter pro gram is the most wide spread [91]. There is
also RNA fold-L-100 pro gram [92], which is ca pa ble
of dif fer en ti at ing real hair pins from pseudo ones
among nu mer ous pre-miR can di dates with free fold -
ing en ergy >23.00 ccal/mol. To pre dict the pres ence
of ma ture miR among pre-miR can di dates there some
com puter pro grams like miRSeeker and miRScan,
which se lect hair pins of 100 nu cleo tides long and to tal
rat ing of >10. miRSeeker [93] and miRScan [94] are
based on the cri te rion of con ser va tism of adult miRs,
thus they se lect can di dates af ter oblig a tory com par i -
son of two re lated hair pins. This is main dis ad van tage
of the men tioned com puter pro grams and thus, the rea -
son of their lim ited ap pli ca tion, es pe cially in the in -
ves ti ga tion on miRs, en coded in the ge nome of vi -
ruses. Bio chem i cal ap proach con firmed that these
com puter pro grams do not iden tify many real miRs,
they se lect the most prob a ble ones, and then “real”
hair pin-can di dates, con tain ing ma ture miRs. How -
ever, pri-, pre-, and ma ture miRs, pre dicted us ing this
method, re quire ad di tional con fir ma tion of the fact
that the pre cur sors are the sub strates for pro cess ing en -
zymes (Drosha, Dicer) [103]. Au thors con sider miRs,
suc cess ful in pass ing this sort of se lec tion, can be
named the real miRs and un suc cess ful ones – pre cur -
sors. Bioinformatical in ves ti ga tion is usu ally con -
firmed by bio chem i cal one (pro files of miRs ex pres -
sion, iso la tion of in di vid ual miRs and their se quenc -
ing) and visa versa.
Par tic i pa tion of miRs in cell pro cess reg u la tion.
What are the re sults ob tained for the last five years
since the dis cov ery of miRs in 2001 [104]?
First of all, all eukaryotic genomes in ves ti gated up
to date con tain miRs genes. The num ber of dif fer ent
miRs in dif fer ent or gan isms is tens and hun dreds in one
or gan ism. E.g. the num ber of miRs genes in hu man ge -
nome is sup posed to ex ceed 1 000 and may even reach
20 000, which is over 3% of en cod ing ge nome ca pac ity,
they may also con trol 30+% of genes [5–7, 105, 106].
Even such small size-wise genomes as genomes of vi -
ruses con tain up to sev eral tens of miRs [8, 107, 108]:
EBV – 32 miRs [8]; rhe sus lymphocryptovirus – 22
miRs; Kaposi sar coma as so ci ated vi rus – 17 miRs; hu -
man cytomegalovirus – 14 miRs; mouse gamma her pes
vi rus – 10 miRs [8]; hu man im mu no de fi ciency vi rus –
10 miRs [107]; Marek’s dis ease vi rus – 8 miRs [108];
sim ian SV40 – 8 miRs; her pes sim plest vi rus – 1 miR
[8]. At the same time one miR may have tens and hun -
dreds of dif fer ent tar gets [5–7, 109]. Dif fer ent tran -
scrip tion fac tors and many other pro tein-fac tors pre vail
among miR tar gets. Pro tein syn the sis is reg u lated in di -
rectly via the pro cesses of tran scrip tion – down-reg u la -
tion (sup pres sion of syn the sis) and up-reg u la tion (res -
to ra tion of syn the sis). How ever, miRs are ca pa ble of
not only sup press ing trans la tion (down-reg u la tion) but
also re stor ing it (up-reg u la tion) [81, 82, 110].
Due to the ef fect on the pro cess of tran scrip tion,
miRs act as real reg u la tors of nu mer ous pro cesses.
Tak ing into ac count the fact that pro files of miRs ex -
pres sion are spe cific to var i ous tis sues, or gans, and
stages of carcinogenesis, it is clear why miRs are in -
volved into con trol and reg u la tion of pro cesses of de -
vel op ment, start ing from embryogenesis [111–115]
and up to adult or gan ism [116–118], pro cesses of dif -
fer en ti a tion [119–121] and cell growth [122–124],
pro cesses of tis sue for ma tion [111, 119, 125] and of
sep a rate or gans [115, 116, 118, 125–127]. miRs con -
trol self-iden ti fi ca tion and dif fer en ti a tion of stem cells
[113–115, 128], pro cesses of pro lif er a tion and
apoptosis [121, 129–134], they take part in the sig nal -
ing sys tems of cells [135], in the reg u la tion of en do -
crine [119, 136] and ner vous [5, 119, 137–141] sys -
tems, they func tion in hematopoiesis [5, 119, 120,
142–144], spermatogenesis [145], immunogenesis
[146–151]. miRs pos si bly take place in al ter na tive
splic ing [152] and to gether with siRNAs in epigenetic
pro cesses [153–156]. They are also in volved into the
me tab o lism of low-mo lec u lar com pounds [157–161]
(amino ac ids [158], lipids [159], glu cose [160], phos -
phates [161]) and in the reg u la tion of cell os motic
pressure [162]. miRs were shown to par tic i pate in the
473
MicroRNA: FROM FUN DA MEN TAL RE SEARCH TO THEIR AP PLI CA TION
reg u la tion of pro tein-pro tein in ter ac tion net work ing in
hu mans [163].
miRs play the sig nif i cant role in vi rus-cell in ter ac -
tions [8]. Gen er ally these are miRs, en coded by large
DNA-con tain ing vi ruses, in te grated into host ge nome,
and retro virus es. Yet this is a whole dif fer ent topic,
which re quires spe cial at ten tion.
miRs and dis eases. Fun da men tal in ves ti ga tion of
biogenesis and func tion ing of miRs at tract spe cial at -
ten tion due to their in volve ment in var i ous pa thol o gies
[105, 121, 131, 155, 164–170], in flam ma tory pro cesses
[171] and stresses [167, 169]. Now a days the meth od ol -
ogy of study ing the ex pres sion pro files of cell miRNAs
in norm and pa thol o gies is in prog ress [104, 106, 121,
131, 172–180]. There also oc cur some pa pers on the
role of miRNA as a tool in the man age ment of em bry -
onic de vel op ment and clas si fi ca tion of hu man tu mours
[121, 174]. On the ba sis of these works the sup po si tion
can be put for ward that pro grams of de vel op ment in all
in ves ti gated or gan isms rep re sent spe cific ex am ples of
miRNA ex pres sion pro files and dis or ders in these pro -
files cor re late with dif fer ent pa thol o gies, in par tic u lar,
vi rus in fec tions [181] and carcinogenesis [106,
132–134, 173–179, 182–192]. Cur rently it has been
shown that neoplasias are char ac ter ized by spe cif i cally
changed pro file of miRNA ex pres sion [121, 173–179,
189, 190, 193–198]. Not only changes in ex pres sion
pro files but also the oc cur rence of spe cific miRs have
been de tected in var i ous tu mours [190, 193, 199–203].
In ter est ingly, both onco genes and tu mour suppressors
may be con sid ered as miRs [131, 176, 177, 185,
199–212].
RNAi-ther apy. To tally new strat egy of mark ing, di -
ag nos tics, pre ven tion, and treat ment of dis eases is be -
ing de vel oped due to the study of new miRs and their
ex pres sion pro files [106, 121, 169, 175–180, 184–187,
203–205, 213–218] which in volves the ap pli ca tion of
ge net i cally and chem i cally mod i fied miRs
(antogomirs) along with siRNAs [191, 219–224]. The
main task for the new gen er a tion of med i cal prep a ra -
tions for dif fer ent types of pa thol o gies is the de ter mi na -
tion of op ti mal mod i fi ca tions of chem i cally syn the -
sized sense and antisense oligonucleotides. De liv ery of
oligonucleotides, vec tor se lec tion, chem i cal mod i fi ca -
tions for pro tec tion from nu cleases, elim i na tion of side
ef fects (in ter feron stim u la tion) – this is the list of the
most im por tant prob lems, wait ing for their so lu tion on
the way to the in tro duc tion of fun da men tal knowl edge
on miRs into med i cal prac tice. In vivo tox ic ity of short
hair pin RNA, con di tioned by the sat u ra tion of me tab o -
lism of endogenic miRs, may hin der the im ple men ta -
tion [225–226]. Re search ers in quire whether these data
would limit ther a peu tic ap pli ca tion of short hair pin
RNA.
John et al. try to an swer this ques tion [227]. These
au thors re vealed that the si lenc ing of tar get genes does
not re sult in sig nif i cant changes in lev els of miR-122,
mir-16, and let-7a, ex pressed in cells of rats and ham -
sters, via the ap pli ca tion of syn thetic siRNA, aimed at
two hepatocyte-spe cific genes (apoliprotein B and fac -
tor VII). Sci en tists con cluded that the ap pli ca tion of
syn thetic miRs should not re sult in the dis or ders in the
or gan ism and thus, antogomirs may be con sid ered “safe
and ef fec tive si lenc ing tool of gene tran scripts”. Stat -
ing on the abovementioned we may sup pose that syn -
thetic mi nor RNA can be ap plied as med i cal prep a ra -
tions. The key role in di ag nos tics and drug dis cov ery
within the new par a digm of de vel op ment of per son al -
ized med i cine, based on RNA-in ter fer ence with miRs
and siRNAs, be longs to miRs [228]. Al though not even
one sin gle com mer cial med i cal prep a ra tion has been
de vel oped and only some are be ing clin i cally tested, fu -
ture mar ket of RNA-in ter fer ence-based drugs is es ti -
mated to be 3.5·109 USD in 2010 and up to 10·1010 USD
in 2015 [228].
Ò. Â. Øèðèíà, Ì. Ò. Áîáðîâñêàÿ, Ý. À. Êîçëîâ
MèêðîÐÍÊ: îò ôóíäàìåíòàëüíûõ èññëåäîâàíèé äî èõ
ïðèëîæåíèÿ
ÌèêðîÐÍÊ – ìàëûå, íåêîäèðóþùèå áåëîê ÐÍÊ äëèíîé 20–30
íóêëåîòèäîâ.  êëåòêàõ ýóêàðèîòîâ ìèêðîÐÍÊ âûïîëíÿþò
ðîëü áèîðåãóëÿòîðîâ ýêñïðåññèè ãåíîâ ÷åðåç ìåõàíèçì
èíãèáèðîâàíèÿ èëè ìîäóëÿöèè ïðîöåññà òðàíñëÿöèè. Öåëü
îáçîðà – ïðîàíàëèçèðîâàòü ìåõàíèçìû áèîãåíåçà è
ôóíêöèîíèðîâàíèÿ ìèêðîÐÍÊ, ñòðàòåãèþ èõ îòêðûòèÿ,
ïðåäîñòàâèòü êðàòêèé ïåðå÷åíü áèîëîãè÷åñêèõ ïðîöåññîâ, â
ðåãóëÿöèè êîòîðûõ ïðèíèìàþò ó÷àñòèå ìèêðîÐÍÊ, à òàêæå
îçíàêîìèòü ñ íîâåéøèìè ïóáëèêàöèÿìè, ïîñâÿùåííûìè
ïðè÷àñòíîñòè ìèêðîÐÍÊ ê ðàçëè÷íûì ïàòîëîãèÿì (îñîáåííî
êàíöåðîãåíåçó) è èñïîëüçîâàíèþ èõ äëÿ ìàðêèðîâàíèÿ,
äèàãíîñòèêè, ïðîôèëàêòèêè è òåðàïèè ðàêîâûõ áîëåçíåé
÷åëîâåêà.
Êëþ÷åâûå ñëîâà: ìèêðîÐÍÊ, áèîãåíåç, ôóíêöèÿ, ïðîôèëè
ýêñïðåññèè, áèîèíôîðìàòè÷åñêîå ïðåäñêàçàíèå, áèîðåãóëÿöèÿ,
êàíöåðîãåíåç, òåðàïèÿ.
474
SHIRINA T. V., BOBROVSKAYA M. T., KOZLOV E. A.
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MicroRNA: FROM FUN DA MEN TAL RE SEARCH TO THEIR AP PLI CA TION
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