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Titia de Lange
Titia de Lange at the Vilcek Prize Ceremony in 2011
Titia de Lange at the Vilcek Prize Ceremony in 2011
Persoonlijke gegevens
Volledige naam Titia de Lange
Geboortedatum 11-11-1955
Geboorteplaats Rotterdam
Nationaliteit Vlag van Nederland Nederland
Wetenschappelijk werk
Vakgebied Moleculaire biologie, Celbiologie, en Genetica
Bekend van
Promotor Piet Borst
Alma mater Universiteit van Amsterdam (Ph.D)
Instituten
Belangrijke prijzen
  • Paul Marks prijs voor kankeronderzoek (2001)
  • Dr. A.H. Heinekenprijs (2012)
  • Canada Gairdner International Award (2014)
http://delangelab.rockefeller.edu/
Portaal  Portaalicoon   Wetenschap & Technologie

Titia de Lange (Rotterdam, 11 november 1955) is de directeur van het Anderson Center voor Oncologie, de Leon Hess professor en het hoofd van het Laboratory Cell Biology and Genetics onderdeel van de Rockefeller-universiteit.[1]

De Lange verkreeg haar Masters aan de Universiteit van Amsterdam in 1981 door onderzoek naar "Chromatin structure of the human ß-globin gene locus", en daaropvolgend haar doctoraat aan dezelfde universiteit in 1985 bij Piet Borst op "surface antigen genes in trypanosomes". In 1985 ging ze werken bij Harold Varmus' laboratorium aan de Universiteit van California in San Francisco. Sinds 1990 is ze onderdeel van de wetenschappelijke staf aan de Rockefeller-universiteit. In 2011 ontving de Lange de "Vilcek Prize in Biomedical Science".[2] In 2013 won ze de Breakthrough Prize in Life Sciences, ter waarde van 3 miljoen dollar, voor haar onderzoek naar telomeren.[3]

In 2000 werd ze correspondent aan de Koninklijke Nederlandse Akademie van Wetenschappen.[4]

Loopbaan

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Titia de Lange studeerde aan de Universiteit van Amsterdam waar ze haar bachelor- en mastersdiploma in de biochemie ontving.[5] Ze haalde ook haar doctoraat aan de Universiteit van Amsterdam terwijl ze werkte voor het Nederlands Kanker Instituut.[5] In 1985 accepteerde ze een positie als doctoraalassistent aan de Universiteit van Californië in San Francisco. In 1990 kreeg de Lange haar eigen laboratorium aan de Rockefeller-universiteit.[5] Momenteel is ze zowel de Leon Hess Professor als de directeur van het Anderson Center for Cancer Research aan de Rockefeller-universiteit.[6] Ze won de Breakthrough Prize in Life Sciences in 2013 voor haar onderzoek naar telomeren, waarbij ze verklaarde hoe telomeren de uiteinden van chromosomen beschermen en wat hun rol is in genetische instabiliteit bij kanker door het complex van moleculen in kaart te brengen dat de strengen aan elkaar lust en ze beschermt. Naast de vooruitgang in het onthullen van de DNA-structuur, heeft haar onderzoek ook geleidt tot meer inzicht in veroudering en kanker.[7]

Onderzoek

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Titia de Lange was eerst van plan om scheikunde te gaan studeren na het afronden van de middelbare school, maar het lage aantal vrouwen onder zowel de leraren als de studenten deed haar besluiten om bilogie te gaan studeren met biochemie als afstudeerrichting.[5] Op de Universiteit van Amsterdam ontmoette ze Richard Flavell, in wiens laboratorium aan het National Institute for Medical Research (NIMR) nabij London ze haar waar ze het equivalent van een scriptie voltooide.[5] Haarr scriptie richtte zich op het identificeren van 'genetic translocation implicated in γβ-thalassemia, a very rare form of thalassemia'.[8] Her research identified a patient with γβ-thalassemia with a DNA translocation that caused the inactivation of the β-Globin gene.[8] de Lange spoke highly of the lab saying "That was where I first saw how science is really done. … It was a very vibrant, competitive, international lab. It was a lot of fun, so that made me stay in science."[5]

De Lange started to gain interest in telomeres while earning her Ph.D. at the Netherlands Cancer Institute.[5] Telomeres gradually became the major focus of her research. After receiving her Ph.D. in 1985, de Lange completed a postdoctoral fellowship at the University of California, San Francisco in Harold Varmus's Lab from 1985 to 1990.[5] While working at UCSF, de Lange continued her work on telomeres. de Lange discovered that sperm cells have telomeres that are several kilobase pairs longer than somatic cells.[9] She also found that tumor cells also have significantly shorter telomeres.[9] This research was significant in establishing the role of telomeres in both aging as well as cancer. Telomeres are repetitive nucleotide sequences at the ends of chromosomes that function as protective elements from improper DNA repair.[10] The nucleotide sequence of telomeres is TTAGGG.[10] As a person ages telomeres are gradually shortened with each round of DNA replication, as not all of the DNA sequence is fully replicated.[10] Chromosome ends are threatened by various pathways, DNA-damage signaling pathways involving ATM or ATR kinase as well as double-strand break repair pathways, Non-homologous end joining or homology-directed repair.[11]

At Rockefeller University her research focused on identifying proteins associated with telomeres and their role in protecting telomeres from processes of DNA repair.[5] In her first several years she dedicated a long amount of time and resources to identifying the major protein components of human telomeres.[5] In 1995, she identified and purified the Telomeric-repeat binding factor protein 1 (TRF1).[12] With the assistance of Bas van Steensel, de Lange conducted various studies on proteins associated with telomeres.[5] She found that TRF1 is crucial in the regulation of the length of telomeres.[13] In her research, she proposed that TRF1 inhibits the action of telomerase.[13] Telomerase is an RNA dependent DNA polymerase that can elongate telomeres and is essential in the maintenance of telomeric DNA.[9][12] Telomerase can counteract the shortening of telomeres, which occurs during the DNA replication process.[14] They also discovered the protein TRF2 and found that it prevents the end-to-end fusing of telomeres, in addition to other functions.[15] One of Titia's major discoveries was the discovery of the t-loop structure of telomeres in her collaboration with Jack Griffith.[16] This was shown through electron microscopy demonstrating that linear telomeric DNA can be remodeled by TRF2 into duplex loops (t loops).[14] This architectural change allows for TRF2 to sequester the ends of telomeres, which function to safeguard telomeres by covering overhanging single strands of DNA.[14] This mechanism protects against the improper activation of DNA damage checkpoints by natural chromosome ends.[14] Previous research had observed that in addition to protecting the ends of chromosomes, telomeric complexes also allow cells to distinguish random DNA breaks and natural chromosome ends.[14]

In 2005, de Lange came to the crucial realization that six telomeric proteins form a dynamic protein complex, that she named shelterin, named for its function of protecting chromosome ends.[17] The six shelterin subunits are: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1.[17] Shelterin subunits are not the only proteins that associate with telomeres but they differ from other proteins by meeting the criteria of not accumulating in areas beside chromosome ends, their function is limited to telomeres, and they are present at telomeres throughout the cell cycle.[17] Shelterin allows for telomeres to be essentially hidden from the DNA damage surveillance, without its safeguarding chromosome ends are inappropriately processed by DNA repair pathways where the telomeres would be mistaken for damaged DNA.[17]

Titia de Lange's research has proven to be invaluable in the area of telomere research and has led to greater understanding for cancer development as well as genome maintenance.[5] Her research has catalyzed more research into the important role of telomeres in tumor development.

Prijzen

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De Lange heeft verschillende prijzen ontvangen:

  • Paul Marks Prize for Cancer Research (2001)
  • Massachusetts General Hospital Cancer Center Prize (2008)
  • AACR Clowes Memorial Award (2010)
  • Vanderbilt Prize in Biomedical Science (2011)[6]
  • Vilcek Prize in Biomedical Science (2011)
  • Breakthrough Prize in Life Sciences (2013)
  • Gairdner International Award (2014)
  • Rosenstiel Award (2017).[8]

Ze is een gekozen lid van verschillende organisaties, waaronder de American Academy of Arts and Sciences, de European Molecular Biology Organization, en de .[6]

References

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  1. ↑ (en) De Lange, Titia, The Rockefeller University De Lange lab. delangelab.rockefeller.edu (October 10, 2018). Geraadpleegd op 10 Oct 2018.
  2. ↑ Titia de Lange receives 2011 Vilcek Prize in Biomedical Science | Newswire. The Rockefeller University (22 februari 2011). Geraadpleegd op 11 april 2018.
  3. ↑ (en) "Cori Bargmann, Titia de Lange win inaugural Breakthrough Prizes worth $3 million", Rockefeller University's Newswire, 20 februari 2013. Geraadpleegd op 11 april 2018.
  4. ↑ Titia de Lange. Royal Netherlands Academy of Arts and Sciences. Geraadpleegd op 19 July 2015.
  5. ↑ a b c d e f g h i j k l Titia de Lange: The Complex Puzzle of Chromosome Ends - Rita Allen Foundation. ritaallen.org. Geraadpleegd op 23 november 2017.
  6. ↑ a b c (en) Titia de Lange, Ph.D.. www.vumc.org. Geraadpleegd op 27 november 2017.
  7. ↑ Breakthrough Prize – Life Sciences Breakthrough Prize Laureates – Titia de Lange. breakthroughprize.org. Geraadpleegd op 16 maart 2019.
  8. ↑ a b c Kioussis, D., Vanin, E., deLange, T., Flavell, R. A., & Grosveld, F. G. (1983). β-Globin gene inactivation by DNA translocation in γβ-thalassaemi. Nature, 306, 662. JOUR. Retrieved from https://dx.doi.org/10.1038/306662a0
  9. ↑ a b c T. de Lange, L. Shiue, R.M. Myers, D.R. Cox, S.L. Naylor, A.M. Killery, H.E. Varmus (1990) Structure and variability of human chromosome ends. Mol. Cell. Biol. 10: 518-527. Retrieved from http://mcb.asm.org/content/10/2/518.long
  10. ↑ a b c Wang, R. C., Smogorzewska, A., & Lange, T. De. (2004). Homologous Recombination Generates T-Loop-Sized Deletions at Human Telomeres, 119, 355–368. Retrieved from https://dx.doi.org/10.1016/j.cell.2004.10.011
  11. ↑ T. de Lange (2011) How shelterin solves the telomere end-protection problem. 75th CSH Symp. Quant. Biol.,75: 167-177. E pub. Jan 5. Retrieved from https://dx.doi.org/10.1101/sqb.2010.75.017
  12. ↑ a b L. Chong, B. van Steensel, D. Broccoli, H. Erdjument-Bromage, J. Hanish, P. Tempst, T. de Lange (1995) A human telomeric protein. Science 270: 1663-1667. Retrieved from doi: 10.1126/science.270.5242.1663
  13. ↑ a b B. van Steensel and T. de Lange (1997) Control of telomere length by the human telomeric protein TRF1. Nature 385: 740-744. Retrieved from doi:10.1038/385740a0
  14. ↑ a b c d e J. D. Griffith, L. Comeau, S. Rosenfield, R. Stansel, A. Bianchi, H. Moss, T. de Lange (1999) Mammalian telomeres end in a large duplex loop. Cell 97: 503-514. (1266). Retrieved from https://dx.doi.org/10.1016/S0092-8674(00)80760-6
  15. ↑ B. van Steensel, A. Smogorzewska, T. de Lange (1998) TRF2 protects human telomeres from end-to-end fusions. Cell 92: 401-413. Retrieved from https://dx.doi.org/10.1016/S0092-8674(00)80932-0
  16. ↑ Titia de Lange - 2013 Breakthrough Price in Life Sciences. Breakthrough Prize. Geraadpleegd op 23 november 2017.
  17. ↑ a b c d T. de Lange (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes and Development 19: 2100-2110. (983). Retrieved from doi: 10.1101/gad.1346005
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{{DEFAULTSORT:Lange, Tita de}} [[Category:1955 births]] [[Category:Living people]] [[Category:Dutch biochemists]] <!--still a Dutch citizen according to her CV --> [[Category:Dutch women chemists]] [[Category:Members of the Royal Netherlands Academy of Arts and Sciences]] [[Category:Rockefeller University faculty|De Lange, Titia]] [[Category:University of Amsterdam alumni]] [[Category:People from Rotterdam]] [[Category:Winners of the Heineken Prize]] [[Category:Fellows of the AACR Academy]] [[Category:University of California, San Francisco alumni]] [[Category:Women biologists]] [[Category:Breakthrough Prize winners]]

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