How the tips of our chromosomes are protected
The Royal Netherlands Academy of Arts and Sciences has awarded the 2012 Dr H.P. Heineken Prize for Biochemistry and Biophysics (USD 150,000) to Professor Titia De Lange, Leon Hess Professor at Rockefeller University in New York (USA). She is receiving the prize for her research on telomeres, the protective DNA sequences located at the tips of chromosomes, which play a crucial role in such processes as ageing and cancer.
Every human cell has a nucleus containing chromosomes. Each of the chromosomes consists of a long, continuous strand of DNA, a chemical ribbon that codes the genetic information passed on from one generation of cell to the next.
The biochemical machinery of human cells is designed to see breaks in the DNA ribbon as “defects” and to glue the loose ends together again. Fortunately, that machinery ignores the chromosome ends. Thanks to Titia De Lange and her research group, we now understand why.
De Lange has demonstrated that the DNA molecules at the chromosome ends arrange themselves into T-shaped loops. The cell machinery therefore does not see them as “breaks” requiring quick repair.
De Lange was the first to suggest that telomeres are shielded from the cell machinery in other ways as well. Her ideas turned out to be correct. She has in fact played a major role in unravelling the protein complex that protects the telomeres – a shield that she has named the “shelterin complex”.
De Lange and her group have even identified two protein molecules within the complex, Terminal Restriction Fragment (TRF) 1 and 2. She has shown that TRF2 suppresses the cell’s repair system at the chromosome ends; if this protein is absent, the cell will “repair” the chromosome ends by mistake.
Previously, she discovered that TRF1 prevents the telomeres in healthy, self-renewing tissue such as skin from becoming shorter at each cell division, and hence from ageing too rapidly. In tumour cells, which divide endlessly without growing “old”, the same protein molecule is frequently overactive.
Telomeres and the shelterin complex play a major role in healthy and sick cells. De Lange’s important and original research will therefore have huge implications for health care.
Titia De Lange was born in Rotterdam, the Netherlands in 1955. She studied at the University of Amsterdam and obtained her PhD at the Netherlands Cancer Institute in Amsterdam, studying under Professor Piet Borst.
She was a postdoctoral fellow in the laboratory of Nobel laureate Harold Varmus at the University of California, San Francisco (UCSF). In 1990 she went to the Rockefeller University in New York. She was appointed professor there in 1997 and since 2011 has been the co-director of the university's Anderson Center for Cancer Research.
Titia De Lange has received many other prizes and distinctions during her career. She is the recipient of the 2011 Vilcek Prize in Biomedical Science, the 2010 AACR Clowes Memorial Award, and the 2008 Massachusetts General Hospital Cancer Center Prize. In 2003, the University of Utrecht awarded her an honorary doctorate.
She is a member of the Royal Netherlands Academy of Arts and Sciences, the European Molecular Biology Organization (EMBO), the American Academy of Arts and Sciences, the American Association for the Advancement of Science (AAAS), and the American National Academy of Sciences.
- Loayza, D., and de Lange, T. (2003). POT1 as a terminal transducer of TRF1 telomere length control. Nature 424, 1013-1018.
- van Steensel, B., Smogorzewska, A., and de Lange, T. (1998). TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401-413.
- Smogorzewska, A., van Steensel, B., Bianchi, A., Schnapp,,G., Schaefer, M. R., Oelmann, S., and de Lange, T. (2000) Control of human telomere length by TRF1 and TRF2. Mol. Cell Biol. 20: 1659-1668.
- de Lange, T. (2005). Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19, 2100-2110.
- Lazzerini Denchi, E., and de Lange, T. (2007). Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature 448, 1068-1071.
The Dr H.P. Heineken Prize for Biochemistry and Biophysics is named after Henry Pierre Heineken, Alfred Heineken’s father, who was himself a biochemist. It is the oldest of the six Heineken Prizes and was first awarded in 1964. Previous laureates include Christian de Duve (later a recipient of the Nobel Prize in Medicine), Piet Borst, Michael Berridge, Paul Nurse (Nobel Prize in Medicine), Andrew Fire (Nobel Prize in Medicine), Alec Jeffreys and Jack Szostak (Nobel Prize in Medicine). The jury for this prize was chaired by Ben Feringa.
The Heineken Prizes will be presented on Thursday 27 September 2012 during an extraordinary meeting of the Royal Netherlands Academy of Arts and Sciences.