Titia de Lange

Last updated

Titia de Lange
Titia de Lange 2011.jpg
Titia de Lange at the Vilcek Prize Ceremony in 2011
Titia de lange

(1955-11-11) November 11, 1955 (age 66)
Alma mater University of Amsterdam (Ph.D)
Known for
Scientific career
Fields Molecular Biology, Cell Biology, and Genetics
Doctoral advisor Piet Borst
Website delangelab.rockefeller.edu

Titia de Lange (born 11 November 1955, in Rotterdam) is the Director of the Anderson Center for Cancer Research, the Leon Hess professor and the head of Laboratory Cell Biology and Genetics at Rockefeller University. [1]


De Lange obtained her Masters on "Chromatin structure of the human β-globin gene locus" at the University of Amsterdam in 1981, and subsequently her PhD at the same institution in 1985 with Piet Borst on surface antigen genes in trypanosomes. In 1985 she joined Harold Varmus's lab at the University of California, San Francisco. Since 1990 she has had a faculty position at the Rockefeller University. In 2011, de Lange received the Vilcek Prize in Biomedical Science. [2] In 2013 she won a Breakthrough Prize in Life Sciences, worth $3 million, for her research on telomeres. [3]

In 2000 she became correspondent of the Royal Netherlands Academy of Arts and Sciences. [4]


Titia de Lange attended the University of Amsterdam where she received her bachelor's and master's degree in biochemistry. [5] She also earned her Ph.D. from the University of Amsterdam while working at the Netherlands Cancer Institute. [5] In 1985, she accepted a postdoctoral fellowship position at the University of California, San Francisco. In 1990, de Lange started her own lab at Rockefeller University. [5] She is currently the Leon Hess Professor as well as the Director of the Anderson Center for Cancer Research at Rockefeller University. [6] She won the Breakthrough Prize in Life Sciences in 2013 for her research on telomeres, illuminating how they protect chromosome ends and their role in genome instability in cancer by mapping the complex of molecules that loops the strands together and protects them. In addition to making headway in revealing the structure of DNA, her research has implications for the understanding of aging and cancer. [7]


Titia de Lange originally wanted to study chemistry after finishing high school in the Netherlands but the lack of women in chemistry among students and teachers alike convinced her to study biology with a biochemistry track instead. [5] In her time at the University of Amsterdam she worked for mentor Richard Flavell at the National Institute for Medical Research where she completed her master's thesis. [5] Her thesis focused on DNA translocation 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] She and her co-investigators, Bas van Steensel and Agata Smogorzewska, 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 de Lange'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.


De Lange is the recipient of several awards including the 2001 Paul Marks Prize for Cancer Research, the 2008 Massachusetts General Hospital Cancer Center Prize, the 2010 AACR Clowes Memorial Award, the 2011 Vanderbilt Prize in Biomedical Science, the 2011 Vilcek Prize in Biomedical Science, the 2013 Breakthrough Prize in Life Sciences, the 2014 Gairdner International Award, and the 2017 Rosenstiel Award. [6] [8]

She is an elected member of multiple organizations including the American Academy of Arts and Sciences, The European Molecular Biology Organization, and the Royal Dutch Academy of Sciences. [6] In 2022 she was elected a Foreign Member of the Royal Society. [18]

Related Research Articles

<span class="mw-page-title-main">Telomere</span> Region of repetitive nucleotide sequences on chromosomes

A telomere is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature most commonly found in eukaryotes. In most, if not all species possessing them, they protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the very ends of the DNA strand for a double strand break.

<span class="mw-page-title-main">Elizabeth Blackburn</span> Australian-born American biological researcher

Elizabeth Helen Blackburn, is an Australian-American Nobel laureate who is the former president of the Salk Institute for Biological Studies. Previously she was a biological researcher at the University of California, San Francisco, who studied the telomere, a structure at the end of chromosomes that protects the chromosome. In 1984, Blackburn co-discovered telomerase, the enzyme that replenishes the telomere, with Carol W. Greider. For this work, she was awarded the 2009 Nobel Prize in Physiology or Medicine, sharing it with Greider and Jack W. Szostak, becoming the first Australian woman Nobel laureate. She also worked in medical ethics, and was controversially dismissed from the Bush administration's President's Council on Bioethics.

<span class="mw-page-title-main">Telomeric repeat-binding factor 2</span> Protein

Telomeric repeat-binding factor 2 is a protein that is present at telomeres throughout the cell cycle. It is also known as TERF2, TRF2, and TRBF2, and is encoded in humans by the TERF2 gene. It is a component of the shelterin nucleoprotein complex and a second negative regulator of telomere length, playing a key role in the protective activity of telomeres. It was first reported in 1997 in the lab of Titia de Lange, where a DNA sequence similar, but not identical, to TERF1 was discovered, with respect to the Myb-domain. De Lange isolated the new Myb-containing protein sequence and called it TERF2.

<span class="mw-page-title-main">Telomeric repeat-binding factor 1</span> Protein-coding gene in humans

Telomeric repeat-binding factor 1 is a protein that in humans is encoded by the TERF1 gene.

<span class="mw-page-title-main">POT1</span>

Protection of telomeres protein 1 is a protein that in humans is encoded by the POT1 gene.

<span class="mw-page-title-main">Tankyrase</span> Enzyme

Tankyrase, also known as tankyrase 1, is an enzyme that in humans is encoded by the TNKS gene. It inhibits the binding of TERF1 to telomeric DNA. Tankyrase attracts substantial interest in cancer research through its interaction with AXIN1 and AXIN2, which are negative regulators of pro-oncogenic β-catenin signaling. Importantly, activity in the β-catenin destruction complex can be increased by tankyrase inhibitors and thus such inhibitors are a potential therapeutic option to reduce the growth of β-catenin-dependent cancers.

<span class="mw-page-title-main">TINF2</span>

TERF1-interacting nuclear factor 2 is a protein that in humans is encoded by the TINF2 gene. TINF2 is a component of the shelterin protein complex found at the end of telomeres.

<span class="mw-page-title-main">ACD (gene)</span>

Adrenocortical dysplasia protein homolog is a protein that in humans is encoded by the ACD gene.

<span class="mw-page-title-main">TERF2IP</span> Protein-coding gene in the species Homo sapiens

Telomeric repeat-binding factor 2-interacting protein 1 also known as repressor activator protein 1 (Rap1) is a protein that in humans is encoded by the TERF2IP gene.

Virginia Zakian is the Harry C. Wiess Professor in the Life Sciences in the Department of Molecular Biology at Princeton University. She is the director of the Zakian Lab, which has done important research in topics such as telomere-binding protein, telomere recombination, and telomere position effects, at Princeton University. She is a fellow at the American Academy of Microbiology and the American Association for the Advancement of Science., and is an elected member of the National Academy of Sciences (2018). Zakian served as the chair of "Princeton's Task force on the Status of Women Faculty in the Natural Sciences and Engineering at Princeton" from 2001-2003, in 2003 Zakian became Princeton University's representative to Nine Universities, Gender Equity Analysis She was elected as a member of the American Academy of Arts and Sciences in 2019.

<span class="mw-page-title-main">Angelika Amon</span> Austrian American academic molecular and cell biologist (1967–2020)

Angelika Amon was an Austrian American molecular and cell biologist, and the Kathleen and Curtis Marble Professor in Cancer Research at the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts, United States. Amon's research centered on how chromosomes are regulated, duplicated, and partitioned in the cell cycle. Amon was elected to the American Academy of Arts and Sciences in 2017.

Xiaowei Zhuang is a Chinese-American biophysicist who is the David B. Arnold Jr. Professor of Science, Professor of Chemistry and Chemical Biology, and Professor of Physics at Harvard University, and an Investigator at the Howard Hughes Medical Institute. She is best known for her work in the development of Stochastic Optical Reconstruction Microscopy (STORM), a super-resolution fluorescence microscopy method, and the discoveries of novel cellular structures using STORM. She received a 2019 Breakthrough Prize in Life Sciences for developing super-resolution imaging techniques that get past the diffraction limits of traditional light microscopes, allowing scientists to visualize small structures within living cells. She was elected a Member of the American Philosophical Society in 2019 and was awarded a Vilcek Foundation Prize in Biomedical Science in 2020.

Telomere-binding proteins function to bind telomeric DNA in various species. In particular, telomere-binding protein refers to TTAGGG repeat binding factor-1 (TERF1) and TTAGGG repeat binding factor-2 (TERF2). Telomere sequences in humans are composed of TTAGGG sequences which provide protection and replication of chromosome ends to prevent degradation. Telomere-binding proteins can generate a T-loop to protect chromosome ends. TRFs are double-stranded proteins which are known to induce bending, looping, and pairing of DNA which aids in the formation of T-loops. They directly bind to TTAGGG repeat sequence in the DNA. There are also subtelomeric regions present for regulation. However, in humans, there are six subunits forming a complex known as shelterin.

Shelterin is a protein complex known to protect telomeres in many eukaryotes from DNA repair mechanisms, as well as to regulate telomerase activity. In mammals and other vertebrates, telomeric DNA consists of repeating double-stranded 5'-TTAGGG-3' (G-strand) sequences along with the 3'-AATCCC-5' (C-strand) complement, ending with a 50-400 nucleotide 3' (G-strand) overhang. Much of the final double-stranded portion of the telomere forms a T-loop (Telomere-loop) that is invaded by the 3' (G-strand) overhang to form a small D-loop (Displacement-loop).

<span class="mw-page-title-main">Telomeric repeat–containing RNA</span> Long non-coding RNA transcribed from telomeres

Telomeric repeat–containing RNA (TERRA) is a long non-coding RNA transcribed from telomeres - repetitive nucleotide regions found on the ends of chromosomes that function to protect DNA from deterioration or fusion with neighboring chromosomes. TERRA has been shown to be ubiquitously expressed in almost all cell types containing linear chromosomes - including humans, mice, and yeasts. While the exact function of TERRA is still an active area of research, it is generally believed to play a role in regulating telomerase activity as well as maintaining the heterochromatic state at the ends of chromosomes. TERRA interaction with other associated telomeric proteins has also been shown to help regulate telomere integrity in a length-dependent manner.

<span class="mw-page-title-main">María Blasco Marhuenda</span> Spanish scientist

María Antonia Blasco Marhuenda, known as María Blasco, is a Spanish molecular biologist. She is the current director of the Spanish National Cancer Research Centre.

<span class="mw-page-title-main">Victoria Lundblad</span> American molecular biologist

Victoria Lundblad is an American geneticist whose work focuses on the genetic control of chromosome behavior in yeast. Many of her discoveries have concerned telomerase, the RNA-containing enzyme that completes the ends of chromosomes. She works at the Salk Institute in La Jolla, California.

Agata Smogorzewska is a Polish-born scientist. She is an associate professor at Rockefeller University, heading the Laboratory of Genome Maintenance. Her work primarily focuses on DNA interstrand crosslink repair and the diseases resulting from deficiencies in this repair pathway, including Fanconi anemia and karyomegalic interstitial nephritis.

Telomeres, the caps on the ends of eukaryotic chromosomes, play critical roles in cellular aging and cancer. An important facet to how telomeres function in these roles is their involvement in cell cycle regulation.

Jan Karlseder is an Austrian molecular biologist, a professor in the Molecular and Cellular Biology Laboratory, the Director of the Paul F. Glenn Center for Biology of Aging Research and the holder of the Donald and Darlene Shiley Chair at the Salk Institute for Biological Studies.


  1. De Lange, Titia (October 10, 2018). "The Rockefeller University De Lange lab". delangelab.rockefeller.edu. Retrieved October 10, 2018.
  2. "Titia de Lange receives 2011 Vilcek Prize in Biomedical Science | Newswire". The Rockefeller University. February 22, 2011. Retrieved April 11, 2018.
  3. "Cori Bargmann, Titia de Lange win inaugural Breakthrough Prizes worth $3 million". Rockefeller University's Newswire. February 20, 2013. Retrieved April 11, 2018.
  4. "Titia de Lange". Royal Netherlands Academy of Arts and Sciences. Retrieved July 19, 2015.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 "Titia de Lange: The Complex Puzzle of Chromosome Ends - Rita Allen Foundation". ritaallen.org. Retrieved November 23, 2017.
  6. 1 2 3 "Titia de Lange, Ph.D." vumc.org. Vanderbilt University Medical Center. Archived from the original on December 1, 2017. Retrieved November 27, 2017.
  7. "Breakthrough Prize – Life Sciences Breakthrough Prize Laureates – Titia de Lange". breakthroughprize.org. Retrieved March 16, 2019.
  8. 1 2 3 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. 1 2 3 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. 1 2 3 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. 1 2 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. 1 2 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. 1 2 3 4 5 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. Retrieved November 23, 2017.
  17. 1 2 3 4 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
  18. "Titia de Lange". The Royal Society. Retrieved May 11, 2022.