Telomerase and Aging

8/12/2019 Telomerase and Aging

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PART I

INTRODUCTION

1.1 The Limitation of DNA Replication Process

The DNA replication process involves DNA polymerases, helicase, in!le"tran#

$in#in! Protein %$P&, an# many other factors. 'hile the DNA polymerases

play a (i! role in creatin! the ne) complementary stran# of the *n)in#in! DNA,

this en+yme cant fi- its o)n limitation. or linear DNA, s*ch as the DNA in

e*/aryotic chromosomes, the fact that a DNA polymerase can only a## ne)

n*cleoti#es at the 0 en# of the *pstream polyn*cleoti#e ma/es a serio*s pro(lem.

The replication set !ives no chance to a## ne) n*cleoti#es *pstream from the

en# of the ne) DNA stran# %Camp(ell, et al., 2332&.

D*rin! DNA replication, synthesis of the la!!in! stran# is #iscontin*o*s an#

re4*ires the presence of some DNA ahea# )hich is to (e serve# as the template of

an RNA primer. $*t, at the e-treme en# of a linear DNA, there can never (e s*ch

a template. After the RNA primer is remove#, DNA polymerase cant a## ne)

n*cleoti#es in the place )here RNA primer formerly locate#. DNA polymerasecant *n#er!o ne) stran# synthesis from 0 to %(ac/)ar#s&. $eca*se some

n*cleoti#es #ont have any pair, they )ill (e #e!ra#e#. As a conse4*ence,

repetitive replication )ill ma/e the ne) DNA molec*les shorten !ra#*ally. o, a

#ifferent mechanism is re4*ire# to solve the pro(lem of replicatin! the en#s of

linear DNA molec*le %trachan 5 Rea#, 1666&.

1.2 Telomere an# Its *nction

Pro/aryote or!anisms have a circ*lar DNA, )hich ma/es the DNA have no en#

an# therefore )ill not (e shorten each time the cell #ivi#e#. 7*/aryote or!anisms

possess a linear DNA form, (y )hich it have en#s that )ill (e shorten each cell

#ivision. 8ean)hile, the e*/aryote or!anisms have *ni4*e n*cleoti#e se4*ence at

the en#s of chromosomal DNA, calle# telomere %Camp(ell, et al., 23329 Anon.,

166:&. Telomere #oesnt possess any !ene9 it consists of a lon! array of repetitive

short n*cleoti#e se4*ence an# some proteins that (o*n# to it. The repetitive

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n*celoti#e se4*ence may vary (et)een species, for e-ample TT;;;; for

Paramecium, TA;;; for Trypanosoma, TTTA;;; for Arabidopsis, an#

TTA;;; forHomo sapiens %trachan 5 Rea#, 1666&.

A small fraction of (acterial chromosomes %s*ch as those in Streptomycessp. an#

Borrelia sp.& are linear an# possess telomeres too, (*t the telomeres are very

#ifferent from those of the e*/aryotic chromosomes in str*ct*re an# f*nctions.

The /no)n str*ct*res of (acterial telomeres ta/e the form of proteins (o*n# to the

en#s of linear chromosomes, or hairpin loops of sin!le"stran#e# DNA at the en#s

of the linear chromosomes.

7*/aryotic telomeres normally terminate )ith 0< sin!le"stran#e#"DNA overhan!

)hich is essential for telomere maintenance an# cappin!. Telomeres form lar!e

loop str*ct*res calle# telomere loops, or T"loops. =ere, the sin!le"stran#e# DNA

c*rls aro*n# in a lon! circle sta(ili+e# (y telomere"(in#in! proteins. At the very

en# of the T"loop, the sin!le"stran#e# telomere DNA is hel# onto a re!ion of

#o*(le"stran#e# DNA (y the telomere stran# #isr*ptin! the #o*(le"helical DNA

an# (ase pairin! to one of the t)o stran#s %Anon., n.#.&.

Telomere acts as a protective cap at the en# of DNA se4*ence. Telomeres appear

to have a role in maintainin! the str*ct*ral inte!rity of a chromosome. If the

telomeres #ont e-ist or lost, the chromosome en#s )ill (e *nsta(le. It may f*se

)ith the en#s from other (ro/en chromosomes, involve in recom(ination events,

or #e!ra#e#. The protection a!ainst homolo!o*s recom(ination an# non"

homolo!o*s en# >oinin! constit*tes the essential ?cappin!@ role of telomeres that

#istin!*ishes them from DNA #o*(le"stran# (rea/s. Also, chromosome en#s

appear to (e tethere# to the n*clear mem(rane, s*!!estin! that telomeres help

position chromosomes an# esta(lish the three #imensional architect*re of the

n*cle*s an#or chromosome pairin! %trachan 5 Rea#, 1666&.

7ven a telomere is e-istin! at the en# of the DNA strin!, telomere consist of

n*cleoti#es. Alon! )ith the limitation of DNA polymerases, it can (e shorten

each time the cell #ivi#es. Critical impact )ill occ*r if the shortenin! reaches the

!ene of the DNA. Telomere shortenin! in h*mans can in#*ce replicative

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senescence )hich (loc/s cell #ivision. This mechanism appears to prevent

!enomic insta(ility an# #evelopment of cancer in h*man a!e# cells (y limitin!

the n*m(er of cell #ivisions %Anon., n.#.&. Accor#in! to this statement, )e /no)

that telomere plays a role to infl*ence the cell a!in!. In spite of that, after a lon!

time of #iscovery, scientists fo*n# that there is one important en+yme that

possesse# (y e*/aryotes that can maintain the len!th of telomeres, calle#

telomerase.

1.0 Telomerase an# =o) It Re!*lates Telomere

Telomerase )as #iscovere# (y Carol '. ;rei#er an# 7li+a(eth $lac/(*rn in

16:. Telomerase, also calle# telomere terminal transferase, is an en+yme ma#e of

protein an# RNA s*(*nits responsi(le for the maintenance of one stran# of the

telomere terminal repeats in most or!anisms. In other )or#s, this en+yme has the

a(ility to len!then telomeres %Chatter>ee 5 A!ra)al, 2310&.

The canonical f*nction of telomerase re4*ires telomerase reverse transcriptase

en+yme %T7RT& )hich a##s telomere n*cleoti#e se4*ence repeats to the

chromosome en#s. $esi#e T7RT, telomerase also nee#s the telomerase RNA

component %T7RC&, )hich provi#es the template for T7RT %Par/inson, et al.,

233:&. T7RT is the /ey protein s*(*nit of the telomerase comple-, possesses

reverse transcriptase %RT&"li/e motifs that #irectly me#iate n*cleoti#e a##ition

%$osoy, et al., 2332&.

Telomerase is a speciali+e# cell*lar RT. It is a ri(on*cleoprotein %RNP& comple-

an# it synthesi+es one stran# of the telomeric DNABnamely, the stran# r*nnin!

to 0 to)ar#s the #istal en# of the chromosomeB(y copyin! a short template

se4*ence )ithin its intrinsic RNA moiety. This action e-ten#s the 0 terminal,

sin!le"stran#e# overhan! fo*n# at the en#s of telomeric DNA. Discovery of this

polymeri+ation action of telomerase esta(lishe# the role of telomerase as a

polymerase that e-ten#s one telomeric DNA stran#. ynthesis of the

complementary stran# of the telomeric repeats is pres*me# to occ*r thro*!h

la!!in! stran# synthesis (y the normal cell*lar DNA replication machinery. The

res*ltin! array of telomeric DNA repeats attracts an# (in#s a set of DNA

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se4*ence"specific (in#in! proteins. These in t*rn (in# a f*rther set of proteins to

(*il# an inferre# hi!her or#er comple- n*cleate# on the telomeric DNA. A##ition

of telomeric DNA onto chromosome en#s (y telomerase serves to co*nter (alance

the losses pre#icte# from the en#"replication pro(lem an# from n*clease action at

telomeric DNA en#s. Interestin!ly, altho*!h the telomerase mechanism for

telomere maintenance is very )i#esprea# amon! e*/aryotes, an# seems to have

appeare# early in e*/aryotic evol*tion, it is not completely *niversal. The

telomerase mo#e of DNA synthesis has some *nprece#ente# properties. Initially,

telomerase RNA )as tho*!ht to have only a template role. All evi#ence in#icates

that the chemical step of the RT DNA polymeri+ation reaction catalyse# (y

telomerase is protein"(ase#, me#iate# (y the catalytic aspartate resi#*es in the RT

active site of T7RT %Anon., n.#.&.

The physiolo!ical roles of the proliferation"#epen#ent telomerase re!*lation in

normal cells remain *nclear. D*rin! e- vivo e-pansion of hematopoietic cells,

telomere len!th #ecreases #espite the presence of telomerase activity, s*!!estin!

that telomerase activity alone is ins*fficient to completely prevent telomere

shortenin! in these cells. =o)ever, the rate of (ase pair loss per pop*lation

#o*(lin! #ecreases in the presence of telomerase activity #*rin! e-pansion,

in#icatin! that telomerase activation may slo) #o)n the rate of telomere erosion

in these cells. Telomerase activation may th*s (e an a#aptive response to protect

e-cessive telomere loss an# possi(ly may help to e-ten# the proliferative life span

of hi!hly re!enerative cells %$o#nar, et al., 166:&.

There are several factors an# a!ents that affect telomerase activity, s*ch as

1. Hormones

everal hormones are involve# in telomerase re!*lation. Re!*lation (y se-

steroi# hormones has (een e-tensively analyse#. or e-ample, estro!en

activates telomerase in estro!en receptor %7R&"positive cells thro*!h the

*p"re!*lation of h*man T7RT %hT7RT& mRNA e-pression.

2. Differentiation inducing agents

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ome #ifferentiation"in#*cin! a!ents can repress telomerase activity in a

variety of cancer cells, pro(a(ly thro*!h in#irect action via in#*ction of

cell*lar #ifferentiation.

3. Growth factors

everal !ro)th factors re!*late telomerase activity in normal an# t*mor

cells. 8ost re!*lation is achieve# (y in#irect actions, (*t some !ro)th

factors may )or/ thro*!h #irect path)ays to re!*late telomerase.

4. Anti cancer agents

ome anticancer #r*!s mo#*late telomerase activity. Cisplatin is a

representative chemotherape*tic a!ent that cross"lin/s DNA (et)een

!*anines. ince telomeres are compose# of !*anine"rich se4*ences, it is

possi(le that cisplatin impairs the telomere str*ct*re, lea#in! to the

inhi(ition of telomerase activity.

5. Histone deacetylase inhibitors

The role of histone #eacetylase %=DAC& inhi(itors in telomerase

re!*lation is comple-. In a variety of normal cells )itho*t telomeraseactivity, =DAC inhi(itors can in#*ce telomerase activity via *pre!*lation

of hT7RT mRNA e-pression in#icatin! that histone #eacetylation is

involve# in transcriptional silencin! of hT7RT in normal cells.

6. ell cycle regulators

ome cell cycle re!*lators are involve# in telomerase re!*lation.

Overe-pression of p0 efectively represses telomerase activity thro*!h

transcriptional #o)n"re!*lation of hT7RT in a variety of cancer cell lines

%$iessman 5 8ason, 166&.

As telomeres infl*ence cell a!in!, the presence of telomerase is #irectly relate# to

the slo)in! #o)n of a!in!. The activity of telomerase can re!*late the len!th of

telomere, therefore the cells life can (e maintaine# an# the cell can #ivi#e a!ain

an# a!ain.

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PART 2

CONT7NT

2.1 Cell A!in! is Relate# to Telomere an# Telomerase Activity

In o*r life, cell is s*ppose# to !ro) an# #ivi#e. This process start from DNA

replication. $*t cell can only #ivi#e *ntil it reaches the limit of replication, calle#

=ayflic/ limit. The limit of replication relates )ith the len!th of telomeres that

present in the chromosome. A telomere can reach a len!th of 1.333 (ase pairs.

=o)ever, each time a cell #ivi#es, a(o*t 2"233 (ase pairs of telomere are lost

#*rin! each #ivision %Aten, 233&. 'hen the telomeres (ecome too short, the

chromosome reaches a Ecritical len!thE an# can no lon!er replicate %$lasco, et al.,

1666&. ome research e-plains that the c*lt*res of cells stoppe# #ivi#in! after an

avera!e of 3"3 c*m*lative pop*lation #o*(lin!s.

Telomerase, as )e /no), is the en+yme that can len!then the telomere. =o)ever,

telomerase have a very lo) %almost *n#etecta(le& activity in most cells of

m*lticell*lar or!anisms. In most m*lticell*lar e*/aryotic or!anisms, telomerase is

active only in !erm cells an# certain )hite (loo# cells. The !erm"line cells m*stretain an *nlimite# cell #ivision to allo) maintenance of !eneration after

!eneration of or!anisms thro*!h evol*tionary history. Lymphocytes retain the

a(ility to #ivi#e an# #ifferentiate as nee#e# for #iverse (iolo!ical p*rposes

%'arner 5 =o#es, 2333&.

$eca*se telomerase is not e-presse# in most cells, the DNA of most somatic cells

in an a#*lt in#ivi#*al is shorter compare# to the yo*n! one %Camp(ell, et al.,

2332&. There are theories that the stea#y shortenin! of telomeres )ith each

replication in somatic %(o#y& cells may have a role in senescence an# in the

prevention of cancer. This is (eca*se the telomeres act as a sort of time"#elay

Ef*seE, event*ally r*nnin! o*t after a certain n*m(er of cell #ivisions an#

res*ltin! in the event*al loss of vital !enetic information from the cellFs

chromosome )ith f*t*re #ivisions.

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As the telomere !ets too short, (esi#e stops proliferatin!, the cell )ont )or/

properly, an# more li/ely to #ie. 'hen some cells in (o#y are #estr*cte#, the

correspon#in! tiss*e )ill !et a pro(lem (y )hich it may loss its f*nction

re!*larly. The non"f*nctionin! tiss*e may affect the anatomical str*ct*re an#

physiolo!ical processes insi#e the (o#y. As the h*man reaches an el#erly a#*lt

sta!e, most of cells have #ama!e# an# there )ill (e a littleno replication to

conserve it.

In the h*man (o#y, there is several #ifferent celerity of cell #ivision. The fastest

#ivision happens in the s/in, thats )hy the a!in! of someone can (e #etecte# (y

seein! the con#ition of hisher s/in, altho*!h the acc*racy may (e 4*estione#.

The me#i*m celerity happens in the liver, s/eletal m*scle, an# a#renal corte-. The

slo)est celerity happene# in (rain, /i#ney, an# heart. Cell a!in! happen earlier in

man (eca*se the telomere lost rate in man is faster than in )oman %$ryan, et al.,

166&.

2.2 Telomerase Pro(a(ly =as an A(ility to Reverse A!in!

Figure 2: two mice involved in an experiment on age-related degeneration

The fact that telomerase can reverse the a!in! process alrea#y fo*n# (y the

researchers after some e-periments are #one to the mo*se %$lasco, et al., 1666&.

One of the e-periments is #one (y 8ariela Gas/elioff an# DePinho %Nai/, 2313&.

In this e-periment, several mice are *se# as o(servation o(>ects. Their con#ition

can represent the con#ition of :3 year"ol# h*mans an# )ere a(o*t to #ie. or the

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first sample %here represente# (y mo*se 1&, they increase the amo*nt of

telomerase in the mo*se (y #evise# an estro!en"(ase# #r*! that )o*l# activate

the animalsF #ormant telomerase !ene, /no)n as T7RT. The #r*!, in the form of a

time"release pellet, )as inserte# *n#er the s/in. A month later, the treate# mice

sho)e# s*rprisin! si!ns of re>*venation. The mo*se !ot ?yo*n!er@ (y the

telomerase en+yme. Hey or!ans starte# to f*nction (etter. The treate# mo*se

re!aine# their sense of smell. The male animalsF once"#eplete# testes pro#*ce#

ne) sperm cells, #ormant (rain stem cells, pro#*cin! ne) ne*rons. The spleen,

testes an# (rain !re) in si+e, an# their mates !ave (irth to lar!er litters. The

treate# animals appear yo*n!er than (efore, tho*!h they #i#nFt live lon!er than

normal mo*se. The f*r in the treate# mice also loo/s more net an# re!enerate#

than in the mice )hich are not treate# %here represente# as mo*se 2&.

ome chemicals may /eep the telomeres lon! in si+e, (y in#*cin! the e-pression

of telomerase !ene. Therefore, the possi(ility of the cell to repro#*ce or #ivi#e

a!ain is increase. It means that the a!in! process can (e slo) #o)n or reverse#.

$*t in other si#e, the e-cess activity of this en+yme can lea# to cancer, (eca*se

this en+yme may ca*se the cell to #ivi#e contin*o*sly an# *nlimite# %Co)ell,

1666&. 7ven tho*!h the researchers have fo*n# that telomerase can reverse a!in!

in the mo*se, f*rther research in h*man m*st (e #one very caref*lly. The research

may lea# to (e very comple- an# re4*ires har# )or/. $*t (y testin! an# testin!,

researchers (elieve they can apply it to the h*man %8ittel#orf, 2310&.

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PART 0

CLOIN;

The DNA replication process, even it is a very comple- process, still have a

limitation that inherite# from !enerations to !enerations. DNA polymerases cant

a## ne) n*cleoti#es from the en# of the e-istin! n*cleoti#es. At the e-treme

en# of a linear DNA, after the RNA primer is remove#, there are no n*cleoti#es

ahea# to (e serve# as a template. Therefore, DNA polymerase cant a## ne)

n*cleoti#es in the place )here RNA primer formerly locate#, ca*sin! some

n*cleoti#es to (e #e!ra#e#. In short, repetitive replication )ill ma/e the ne)

DNA molec*les shorten !ra#*ally %trachan 5 Rea#, 1666&.

7*/aryote or!anisms face this pro(lem (y havin! *ni4*e n*cleoti#e se4*ence at

the en#s of DNA, calle# telomere. Telomeres consist of lon! repetitive n*cleoti#e

se4*ence. Telomere #oesnt possess any !ene, an# acts as a cap that protects the

DNA !enes from #e!ra#ation each cell #ivision %Camp(ell, et al., 23329 an#

Anon., 166:&. Telomere itselfB(eca*se it is nat*rally a se4*ence of n*cleoti#esB

also shorten each cell #ivision. If the telomeres have (een too short %the !enes

nearly e-pose#&, the cell stops #ivi#in! an# more li/ely to #ie. This sit*ation is

calle# cell a!in!. If this is happen, the correspon#in! tiss*e )ill (e a!in! too. The

cells are #yin! an# there are a littleno cell #ivision to maintain it. If the tiss*es are

a!in!, of co*rse the or!anism is a!in! too. Thats )hy telomere seems to have an

important role in h*man nat*ral life span %$ryan, et al., 166&.

cientists have fo*n# an en+yme calle# telomerase that can len!then the telomere.

Unfort*nately, telomerase only activate# in several cells, s*ch as !erm cells an#

lymphocyte cells %'arner 5 =o#es, 2333&. This ma/es the scientist )on#er, if

telomerase activity can (e increase# in other cells, co*l# it reverse a!in!

7-periments #one to the mice sho) that telomerase activity can ma/e ol# mice

re!ain its health an# maintain its appearance %Nai/, 2313&. Until no), there are no

e-periments #one to h*man to prove that telomerase can slo) #o)n the cell a!in!

or even reverses a!in! %8ittel#orf, 2310&. This fact opens the !ate for scientists to

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o(serve this #eeper on h*man, an# ma/es a ne) hope that molec*lar (iolo!yB

*sin! telomeraseBcan (e applie# to maintain the healthy life of el#erly people.

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R77R7NC7

Anon., 166:. Telomerase Discovery. Te Futurist! 02%0&, p. 21.

Anon., n.#. Telomere Function" JOnlineK

Availa(le at http))).ne)s"me#ical.nethealthTelomere"*nction.asp-

JAccesse# Decem(er 2310K.

Aten, D., 233. #ell Biology" s.l.$iome#ical Comm*nications ;ra#*ate Pro!ram,

o*th)estern 8e#ical Pro!ram.

$iessman, =. 5 8ason, G., 166. Telomere 8aintenance 'itho*t Telomerase.

#romosoma! Mol*me 13, pp. 0"6.

$lasco, 8. A., ;asser, . 8. 5 Lin!ner, G., 1666. Telomeres an# Telomerase.

$enes and %evelopment! Mol*me 10, pp. 200"206.

$o#nar, A., *elette, 8., rol/is, 8. 5 =olt, ., 166:. 7-tension of Life"pan (y

Intro#*ction of Telomerase into Normal =*man Cell. Science! Mol*me 26, pp.

06"02.

$osoy, D., Pen!, ., 8ian, I. . 5 L*e, N. ., 2332. Conserve# N"terminal 8otifs

of Telomerase Reverse Transcriptase Re4*ire# for Ri(on*cleoprotein Assem(ly

In Mivo. Te &ournal '( Biological #emistry!pp. 1"0:.

$ryan, T. et al., 166. Telomere 7lon!ation in Immortal =*man Cells 'itho*t

Detecta(le Telomerase Activity. Te )*B' &ournal! 1%1&, p. 23Q2:.

Camp(ell, N. A., Reece, G. $. 5 8itchell, L. $., 2332.Biologi" th e#. Ga/arta

7rlan!!a.

Chatter>ee, . 5 A!ra)al, ., 2310. Telomerase Reverses A!in!.)veryman+s

Science! LMII%&, pp. 06"02.

Co)ell, G., 1666. Telomeres an# Telomerase in A!ein! an# Cancer.Age! Mol*me

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8ittel#orf, G., 2310. Telomere $iolo!y Cancer ire)all or A!in! Cloc/.

Biocemistry ,*oscow! :%6&, pp. 13"133.

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httponline.)s>.comne)sarticles$13331232:30:326236

221:3

JAccesse# Decem(er 2310K.

Par/inson, 7., itchett, C. 5 Cereser, $., 233:. Dissectin! the Non"canonical

*nctions of Telomerase. #ytogenetic and $enome /esearc! Mol*me 122, p.

20Q2:3.

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Telomerase and Aging

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