Telomere T elomere Bio Bio & Cancer Paper
Telomere Biology and Cancer Introduction Telomere Telomere biology biology is an area of heavy research research in hopes of nding nding a cure cure for cancer. cancer. Cancer is known to bypass regulatory regulatory systems during cell proliferation which allow the cells to divide uncontrollably. uncontrollably. According to the review review The Role of Telomere Biology in Cancer, telomeres and the enyme telomerase play a signicant role in the development of cancer. !n this review" a variety of ways in which telomere biology can be used to initiate and possibly develop treatments treatments for cancer are presented and evaluated. The survival survival of a species species necessitates genomic stability# it ensures that all re$uired information is passed on from one generation to the ne%t" and so on. ukaryotes re$uire a comple% and e'cient ()A repair mechanism" which is time*sensitive time*sensitive in its onset and duration. ukaryotic genome is organied in a linear fashion + a conguration that lends itself to the problems of tail*end maintenance" and the need to di,erentiate these tail*ends" called telomeres -literally# the ending part/0" from ()A double*strand breaks -(1Bs0. (1Bs are routinely employed in initiating cell death in cancer treatment. Telomeres Telomeres are found found at ends of linear linear chromosomes chromosomes and are are an e%tension of the parent parent ()A strand which allows for ()A polymerase 2 to complete the lagging strand during ()A replication. replication. ()A polymerase polymerase 2 has a ()A primase subunit that enables it to supply its own primer. After applying the primer to the telomere" the polymerase can then nish the se$uence. Preserving Preserving ()A is important since since the loss of genetic information can lead lead to apoptosis of the cell or disease" such as cancer. There are are a handful handful of mechanisms mechanisms that support the integrity of of telomeres. telomeres. The enyme telomerase is responsible for retaining the length of telomeres which are shortened after each round of cell division. division. !f telomeres are are too short or too long" this may lead to senescence" apoptosis apoptosi s or cancer. cancer. The latter has become evident in fast growing cells which trend to have high levels of telomerase e%pression -30. ()A*damage response proteins as well as other protein comple%es aid in protecting telomeres. 4or instance" ()A*repair proteins along with the shelterin comple% the formation of t*loops of telomere ends during 53 phase phase of cell cycle -60. These t*loops are believed believed to further protect the telomeres from damage by concealing the end of the ()A. 7owever" if any of these proteins were to falter8 this could lead to a loss of telomere signaling" an increase in telomere*free chromosomes or the proteins themselves may inhibit telomerase -60.
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Telomere Bio & Cancer Paper
Telomeres are a very elaborate arrangement# they are nucleoprotein comple%es that physically cap/ the chromosome9s ends and vary in length between : to ;:kb in humans. !t has a ()A repeat se$uence of :9 TTA555 69 he%amer -referred to as the 5*tail/8 outwards from the centromere0 that overshoots its complimentary AATCCC se$uence. This overhang bends on itself to form a lariat*like ()A loop -t*loop/0" while the 69 5*end forms a d*loop by e%tending into the t*loop. Thus" a secondary ()A structure is constructed" which inherently prevents the 5*tail from being recognied as a ()A (1B and prevents access to ()A damage response -((<0 enymes and nucleases. An almost cardinal rule of ()A replication is incomplete replication of the lagging strand" followed by post*replicative degradation of the :9 strand. This causes telomeres to be shortened after every cell cycle. 1uccessive cell replications -aging0 result in the inability of telomeres to form a t*loop" triggering chromosome fusion" e%onuclease degradation" and=or ((<. There are a variety of ()A lesions and cells initiate a ((< via a signal transduction mechanism. ((< regulates transcription and gathers and deploys respective ()A repair apparatus to these lesions in response to metabolic conditions" and manages cell fate decisions by introducing cell cycle checkpoints. The eventual goal for ((< is to maintain genomic integrity by preventing replication of cells with damaged ()A. (eciencies in ((< increase the predisposition of cancer and neurodegeneration. >f these ()A lesions" the (1Bs have particular signicance + while they are readily caused by ioniing radiation" they have many endogenous sources# e%posure to free radicals during ()A replication" errors made by the enymes involved" and limited supply of certain nucleotides" enymes" cofactors" and other proteins. (i,erent types of chemical moieties are associated with (1Bs that di,er from the regular :9 phosphate and 69 hydro%yl ends allowing a wide variety of enymatic activity to be available to prepare (1Bs for repair8 however" they may not be able to perform their re$uisite repair tasks as the comple%ity of the ()A lesions increase. !n these events" nucleases are employed to cleave the damaged ()A se$uences. Cells have developed ve pathways for ()A repair. (1Bs" which arise from single* stranded ()A -ss()A0 replication and free radicals" are repaired through homologous recombination -7<0 and non*homologous end ?oining -)7@0. 1ingle* stranded breaks -11Bs0 are repaired via three e%cision repair pathways# mismatch repair -<0" nucleotide e%cision repair -)<0" and base e%cision repair -B<0. hen a (1B is detected" the cascade of events is triggered by AT -ata%ia*Telangiectasia* utated0" AT< -AT and
7*kinase*like kinases0" and ()A*P -()A*dependent protein kinase0. (uring late 53 and 1 phases" availability of a second ()A copy triggers 7<" and while the repair is error*free" it re$uires the action of additional proteins +
The Key Players and Factors in the Telomere Story (vis-à-vis Cancer) Page 2 of 9
Telomere Bio & Cancer Paper
!n mammals" there are si% dedicated telomere* specic proteins# Telomeric T;0. Collectively" these are the shelterin comple%. T<4; and T<43 bind directly to the telomere double strand" while P>T; binds to the single stranded telomeric overhang and protects the 69 5*tail. TPP; forms a comple% with P>T; while binding with ss()A" and may also be involved in recruiting telomerase. T!)3 links ss()A and ds()A binding comple%es" most probably at the d*loop formation.
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Telomere Bio & Cancer Paper
Telomerase is a specialied multisubunit ribonucleoprotein -<)P0 that elongates telomere se$uences onto chromosome ends. !t has two conserved subunits# T7 at end of the 5*tail overhang and" using TP;E" and 5A<; -5ly*Arg FA; and )>FA 6 proteins -not identied in the gure0" these catalye pseudouridylation -isomeriation of uridine where ribose is attached to C:" not );0 of r<)A" believed to be re$uired for correct processing or tra'cking of T modication" and transcription regulation. hen the pontin=reptin association with T
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Telomere Bio & Cancer Paper
their heterochromaticity + methylation of histones" acetylation + change the conformation of these chromatins resulting in increased telomere length. This becomes increasingly important in the incidence of cancer in humans where there is a signicant dearth of telomerase.
"hen Telomeres and Telomerases go #$ry !n the absence of a telomere9s protective mechanism" through disruption of the shelterin components or normal attrition due to replication" causes the ends of chromosomes to mas$uerade as a (1<" triggering the cell9s ((<. !t has been found that AT and=or AT< help coordinate the action of a ((< on a dysfunctional telomere. As T<43 depletes" it triggers AT. AT< is triggered either by P>T; degradation -69 telomeric overhang is deprotected0 or T<4; depletion. hen upstream ((< is dysfunctional" tumor*prone phenotypes may emerge. Foss of AT function causes Ata%ia*Telangiectasia -A*T0" a neurodegenerative disease that a,ects the nervous system" immune system and some organs. (ysfunctional telomeres are highly interesting" as they can trigger either of opposing pathways in promoting genome stability or compromising it. ther senescence stimuli include 7(AC -histone deactylase0 inhibitors" which help open up the chromatin" activate AT and the tumor suppressor p:6. >ncogenes deliver a strong mitogenic signal causing errors in ()A9s replication of origins and replication forks" whereby cells e%perience senescence" and triggers a persistent ((<. 7owever" cells can also senesce without a ((< being triggered -mechanism not clearly known0. The propensity of malignant cancers to occur and proliferate increases with age. The incidence of senescent cells increases with age in a variety of tissues" and increasingly so in mitotically*able tissues. These very tissues" in*turn" help trigger cancer cells. 1enescent cells also develop a secretory phenotype -1A1P0 and much of what they secrete -e.g. growth* related oncogene" cytokines interleukin*I0 is associated with aggressive cancer cells. !n T
Telomere Bio & Cancer Paper
to end*to*end telomere fusion or recombination between sister telomeres. The incidence of tumorous growth" when evaluating colon and breast tissue" has demonstrated an increase in fusion and recombination. !n breast cancer" while analying both tissue samples and cell cultures" there is support for telomere degradation leading to an outgrowth of cancerous cells where telomerase is present. There have been conHicting conclusions from various studies evaluating telomere attrition + some determining that decreased telomere length is associated with higher cancer risk" a longer length is associated with increased cancer risk" and some no association between length and cancer risk. hile these studies do employ di,erent methodologies" it is clear that the telomere role in cancer propagation or prevention is conte%t dependent. !n human cancer" telomere dysfunction is involved in early chromosome instability" long* term cellular proliferation" and possibly other processes related to cell survival and microenvironment. Telomeres constitute an attractive target for the development of anti* cancer drugs. !n particular" individual protein components of the shelterin comple% are promising candidate targets for cancer therapy.
&ther 'echanisms y $hich Telomerase imacts Cancer !t has been established that an increased presence of telomerase increases the incidence of tumors. This is accomplished by preventing telomere attrition" thereby promoting cell division. !n e%perimentation" activation or over*e%pression of telomerase is achieved by an over* or under*e%pression of T
#lternative *engthening o+ Telomeres !t has been observed in 7eFa cells that even in the absence of telomerase" there is an appreciable level of telomere length maintenance being e%ercised. Telomerase*negative cancers adopt a variety of di,erent mechanisms to maintain telomere length" referred to collectively as AFT. These are usually found in pancreatic tumors" sarcomas" and brain tumors. AFT cells contain a wide range of telomere lengths from the e%tremely long to the e%tremely short. The incidence of recombination at telomeres" as well as interchromosomal telomere recombination has been found to be very high. T*1C levels are also elevated. There is a big Page , of 9
Telomere Bio & Cancer Paper
overlap between the proteins re$uired for recombination and for telomere maintenance in these cells. AT
Telomere-ased Theraetic Strategies
Our evaluation of paper’s results After reading this article" we had a much better understanding of why a cure for cancer is so di'cult to discover.
The telomere biology of mice is di,erent then that of human telomere biology" how can we conclude that the results from the e%periments with mice are relevant to human biologyLL
Conclusion The study of telomere biology has enhanced our knowledge of the origin of cancer and has given us possible avenues to e%plore for inhibiting its progression. 7owever" these studies are far from completeM very possible tactic has its pluses" minus and unknown side reactions. 1tudies have shown that the enyme telomerase is a key player in cell proliferation and that its activity is increased by J:N in human cancers -60. Therefore" the inhibition of telomerase activity seems to be a likely option for a therapeutic strategy8 however" four potential problems arise. 4irst" in the absence of telomerase" the telomeres become too short for ()A polymerase 2 to duplicate the ends of the chromosomes. The telomere depleted chromosomes then trigger a ()A*damage response which usually results in senescence. ven though the cells may not be dividing any longer" they may secret a to%in that causes inHammation which later may result in cancer -60. 1econdly" the cancer cells could bypass regulatory mechanisms via AFT pathways and facilitate the growth of cancerM Thirdly" there is the uncertainty that all cancers will react the same way to the telomerase inhibitor" plus" there could be unforeseen side a,ects. And lastly" there is the issue of how to administer the inhibitor to ?ust the targeted cells. !f the cancer formed due to a depletion of the telomere" then" the healthy Page . of 9
Telomere Bio & Cancer Paper
cells with telomerase activity may survive. Conversely" what if the cancer was caused by the telomeres being too long" then this approach would be irrelevant. Another possible therapeutic strategy would be to disrupt the function of the telomere itself. ven though this approach may be $uicker then waiting for the telomere to shorten" this method faces similar dilemmas as with using a telomerase inhibitor8 such as" to%icity" the possible use of AFT pathways and targeting administration. The telomere*disrupting agents would not be able to distinguish between healthy and cancerous cells8 therefore" the survival of normal cells would be a,ected as well. A third option discussed was the hopeful strategy with the use of telomerase* targeted immunotherapy. Cytoto%ic T lymphocytes -CTF0 can recognie antigens and T
Bibliography ;. OAta%ia*telangiectasia.O 5enetics 7ome
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