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  • Scientists discover how a well-known protein repairs broken DNA ends | Newswire
    double stranded breaks in need of repair that is they engage the end to end fusion pathway Using digital cell imaging the team has now become the first to create live video footage of how telomeres move around in the nucleus when uncapped In their work de Lange and her team genetically deleted a protein from the shelterin complex thus exposing the ends of the linear chromosomes By marking the telomeres with a fluorescent protein and recording their movement in live mouse cells the researchers saw that the telomeres became more mobile when they were unprotected moving faster and exploring a larger region of the nucleus You go from a rather dull party to a wild dance where the telomeres start meeting one another says de Lange The party really gets going But when the researchers removed 53BP1 from the cells the movies revealed that the telomeres no longer exhibited this ramped up mobility The effect is quite striking says first author Nadya Dimitrova a graduate student in the lab Without 53BP1 we don t see this dynamic behavior anymore The ends are much more restricted in their mobility It s not that the ends can t fuse the fusion machinery is intact It s just that the ends don t get close enough to each other The findings not only point to 53BP1 as the main driver of telomere mobility but show that this mobility is important for the repair of uncapped telomeres The researchers are quick to point out that the repair process of dysfunctional telomeres is not the same as that of internal chromosomal double stranded breaks At dysfunctional telomeres there is only a single DNA end whereas internal breaks lead to two ends that are close together and do not need to search for a fusion

    Original URL path: http://newswire.rockefeller.edu/2008/10/24/scientists-discover-how-a-well-known-protein-repairs-broken-dna-ends/ (2016-02-13)
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  • Eroded telomeres are behind a rare premature aging syndrome | Newswire
    have shortened telomeres green and develop a rare yet fatal premature aging syndrome called dyskeratosis congenita Sufferers of the disease called dyskeratosis congentia tend to have problems in tissues in which cells multiply rapidly skin hair nails tongue gut and bone marrow and usually die between the ages of 16 and 50 from bone marrow failure or the inability to replenish their blood cells According to some estimates dyskeratosis congenita has only been diagnosed in 70 individuals since it was first described in 1906 But the disease is probably much more frequent than previously inferred says de Lange as it is part of a spectrum of disorders with diverse clinical manifestations such as anemia and lung fibrosis Although patients were found to have severely shortened telomeres at the time of diagnosis perplexing findings emerged that left researchers wondering whether dyskeratosis congenita was a telomere based disease after all When bits of DNA are lost from telomeres during each cell division telomeres are partially rebuilt with an enzyme called telomerase However when researchers genetically engineered mice that didn t produce telomerase the mice had very short telomeres but didn t show any signs of the disease particularly its hallmark bone marrow failure De Lange and her former graduate student Dirk Hockemeyer who graduated in 2007 took a different approach They made mice that lack POT1b a protein that protects telomeres from getting degraded Without POT1b mice do not show the signs and symptoms of dyskeratosis congenita but the telomeres shorten so fast that telomerase is incapable of keeping up with the loss But without POT1b and reduced telomerase activity mice develop the major hallmarks of the disease and die of bone marrow failure When the mice that lacked POT1b were bred with mice that lacked telomerase the offspring died Dirk s

    Original URL path: http://newswire.rockefeller.edu/2008/07/30/eroded-telomeres-are-behind-a-rare-premature-aging-syndrome/ (2016-02-13)
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  • dyskeratosis congentia | Newswire
    obsessed researchers at Rockefeller University reveal the molecular defect behind a rare yet fatal premature aging syndrome findings that may ultimately help scientists disentangle which genes play a role in the normal aging process from those involved in age related disease More Tags dyskeratosis congentia telomeres Titia de Lange Search for Categories Science News Awards and Honors Campus News Grants Gifts Topics Video Archive 2015 2014 2013 2012 2011 more

    Original URL path: http://newswire.rockefeller.edu/tag/dyskeratosis-congentia/ (2016-02-13)
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  • Mammalian protein plays unexpected role in cell division, and perhaps cancer | Newswire
    ultimately perish or accumulate mutations and form tumors This research and its surprising conclusion appears in the December 28 issue of Cell When de Lange and Hiroyuki Takai a postdoc in her lab found that Tel2 had no obvious function in mammalian telomeres they almost dropped the project But then Takai noticed that cells without Tel2 were unable to detect damage in their DNA a function carried out by two members of the PIKK family ATM and ATR So Hiro decided to measure their levels in these Tel2 knockout mice and saw that within three or four days the two proteins were gone says de Lange who is also Leon Hess Professor at Rockefeller After measuring the four other PIKKs de Lange and Takai found that only PIKKs disappeared in these cells suggesting that Tel2 specifically targets this family of signal transducers Takai and de Lange determined that Tel2 prevented the degradation of these proteins by using a laborious time honored technique called pulse chase labeling With this technique they found that cells without Tel2 were able to synthesize the six proteins but were unable to keep them around Tel2 doesn t affect their synthesis but their stability The group further showed that Tel2 stabilizes each of these six PIKKs by binding to a region common to all of them In addition to ATR and ATM the PIKK family includes SMG1 TRRAP DNA PKcs and mTOR all kinases that regulate central pathways of enormous importance to human disease says de Lange In particular tumor cells depend on mTOR to survive and to a large extent ATR and ATM for some time now mTOR has been a target in clinical trials to combat cancer We are excited about the possibility of using our findings to manipulate PIKKs in tumor cells and

    Original URL path: http://newswire.rockefeller.edu/2008/01/18/mammalian-protein-plays-unexpected-role-in-cell-division-and-perhaps-cancer/ (2016-02-13)
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  • Two proteins found on telomeres control DNA damage response pathways | Newswire
    from these pathways in turn play a crucial role in DNA repair The two proteins are part of a protein complex called shelterin which binds specifically to telomeres and ensures that chromosome ends do not elicit a DNA damage response When there is a break in a chromosome or when telomeres shorten the cell activates a response and stops dividing reallocating its resources to repair the DNA Proteins called DNA damage factors are recruited to the site and form foci that can be observed in the microscope One of these pathways ATM looks for double stranded breaks while the second ATR looks for single stranded DNA which can form where one strand has begun to degrade These series of events can happen anywhere on the chromosome but Lazzerini Denchi and de Lange found that the shelterin complex has a built in mechanism to initiate these DNA damage response pathways specifically at telomeres When Lazzerini Denchi and de Lange deleted TRF2 from the shelterin complex they saw that this deletion elicited the formation of DNA damage foci at telomeres indicating that the cell was summoning its resources to repair the damaged telomeres However when they deleted TRF2 in cells that lacked ATM kinase the primary signaling factor of the pathway they didn t see any response This really surprised us says de Lange We thought that both pathways would be activated but since we didn t see a damage response after removing both ATM kinase and TRF2 that meant that the ATR pathway wasn t activated So something else was controlling the ATR pathway Since POT1 is the only protein within the shelterin complex that binds to single stranded DNA and single stranded DNA activates the ATR pathway de Lange and Lazzerini Denchi thought POT1 was a good candidate When they

    Original URL path: http://newswire.rockefeller.edu/2007/08/09/two-proteins-found-on-telomeres-control-dna-damage-pathways/ (2016-02-13)
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  • Living cells prosper without telomeres | Newswire
    shelterin cells mistake the exposed chromosome ends for sites of DNA damage The DNA damage signal elicited by dysfunctional telomeres usually kills cells If cells try to repair the chromosome ends they make such a mess of their chromosomes that they can no longer divide But all our previous work on shelterin was done in tissue culture cells that are continuously dividing de Lange says We wanted to look at telomeres in cells that aren t dividing and nothing prepared us for the outcome The researchers chose mouse liver cells as the subject because it s easy to delete specific genes in the liver and although liver cells do not normally divide they will if the organ is injured When de Lange and her colleagues Eros Lazzerini Denchi and Giulia Celli deleted the essential shelterin protein TRF2 they anticipated telomere dysfunction and cell death just as they had observed in cell culture And at first everything happened as expected There was a brief DNA damage response and the telomeres were repaired inappropriately But the cells did not die and Eros told me that the mice were fine de Lange says Further examination of the cells revealed that all of the chromosomes were stuck together in long trains yet gene expression was normal producing all the enzymes the liver needs to dissolve fats break down hormones and do its other metabolic work Even more surprising was the outcome when Lazzerini Denchi forced the regeneration of the livers by performing partial hepatectomy In this well established procedure the remaining liver cells divide several times and regenerate liver mass in that way Again they found that absence of shelterin was not harmful and the mice regenerated their livers with no difficulty To say we were surprised is an understatement de Lange says When

    Original URL path: http://newswire.rockefeller.edu/2006/11/10/living-cells-prosper-without-telomeres/ (2016-02-13)
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  • Evidence of rapid evolution is found at the tips of chromosomes | Newswire
    the telomeres Because POT1 binds to single stranded telomeric DNA present at the very end of the chromosomes the de Lange lab asked how POT1 contributes to the protection of telomeres We had previously removed TRF2 from mouse cells and seen many dramatic phenotypes says de Lange all of the telomeres ligate together there is a massive DNA damage response and the cells basically die We argued that if the function of TRF2 was to bring POT1 to the DNA then we should observe the same phenotype if we removed POT1 To determine if this was the case graduate student Dirk Hockemeyer the first author of the paper decided to remove the POT1 gene from mice Humans have one POT1 gene so de Lange and Hockemeyer were more than a bit surprised when they found two POT1 genes in the mouse genome Both genes are ubiquitously expressed and both are at telomeres says de Lange Nothing prepared us for the possibility that these two genes which we called POT1a and POT1b were doing different things at the telomere But the mice showed that POT1a and POT1b did indeed serve different functions Without POT1a the cells showed a massive DNA damage response which did not happen in cells missing POT1b In contrast cells without POT1b had strangely altered telomere structures something that didn t occur when POT1a was removed Wherever we looked the two phenotypes were different de Lange says To make it more extreme the POT1b knockout mouse was alive and well but the POT1a knockout mouse was embryonic lethal at a very early stage The other surprise came from the POT1a b double knockout mouse While it had a very strong DNA damage response similar to cells missing TRF2 there was hardly any chromosome end fusion This result led

    Original URL path: http://newswire.rockefeller.edu/2006/08/02/evidence-of-rapid-evolution-is-found-at-the-tips-of-chromosomes/ (2016-02-13)
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  • How Aging Cells Retire | Newswire
    showed that telomeres don t stick out as previously believed but form closed loops called t loops They proposed that t loops act to cap or protect chromosome ends But just how shrinking telomeres trigger an aging cell to retire has puzzled scientists until now Professor Titia de Lange left Agata Smogorzewska and Jan Karlseder propose that old cells stop reproducing when their shrinking telomeres become too short to function not when they completely disappear as scientists previously believed According to the Rockefeller researchers a cell ceases to divide when its telomeres become too short to protect the ends of chromosomes and not when they completely run out as many scientists previously believed They show that a protein called TRF2 can allow old cells to continue replicating even when their telomeres are abnormally short TRF2 helps critically short telomeres function better and this in turn allows these cells to live just as long as cells with longer telomeres says Karlseder This is significant because it means that a change in the protected status of telomeres and not their complete loss is what triggers senescence Perhaps the short telomeres in old cells are no longer able to form the protective loops and it is the opened telomeres that trigger senescence If scientists can figure out what triggers a cell to enter senescence they might be able to delay this process for the treatment of diseases in which a cell ages too fast such as dyskeratosis congenita Bloom and Werner syndromes The findings also may lead to new strategies for regenerating cells that are lost in degenerative diseases Conversely it may one day be possible to destroy the immortal cells of cancer which have figured out a way to keep their telomeres long by manipulating them into an early retirement Aging and cancer are flip sides of the same coin says Karlseder The trick for scientists is to be able to influence one without adversely affecting the other Since the 1970s scientists have known that the ends of every chromosome in a cell contain identical regions of DNA repeats that make up the telomeres But it wasn t until recently that scientists realized that these fragile chromosomal ends hold secrets to aging and cancer This insight arose from the finding that an enzyme called telomerase elongates the telomeres of both reproductive cells and cancer cells and as a result extends the life span of these cells In the current study the scientists add another chapter to this story Initially they found that human cells made to overproduce TRF2 a protein they first identified in 1997 exhibited an increase in the rate at which their telomeres shortened While normal cells lose their telomeric DNA at a rate of 100 units per cell division cells overproducing TRF2 exhibited a rate of up to 180 units per cell division But these same cells entered senescence when their telomeres were shorter than normal thereby compensating for the increased rate of shortening Moreover in some cases these

    Original URL path: http://newswire.rockefeller.edu/2002/03/28/how-aging-cells-retire/ (2016-02-13)
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