Heads of Laboratories
Leon Hess Professor
Laboratory of Cell Biology and Genetics
delange@rockefeller.edu
Life depends on the stable maintenance of genetic information. But in eukaryotic cells, this stability can be threatened when the ends of chromosomes are mistaken for DNA breaks. Dr. de Lange’s lab studies telomeres, the elements that protect chromosome ends from unnecessary repair and mediate their replication.
Dr. de Lange’s lab focuses on mammalian telomeres, which are made up of long arrays of double-stranded TTAGGG repeats that end in a single-stranded overhang. Telomerase, an enzyme that recognizes this overhang, adds TTAGGG repeats to chromosome ends and thereby counteracts telomere shortening each time a cell divides. Telomerase is absent from most human cells and as a consequence, many somatic cells age and eventually die due to depletion of their telomere reserve. Cancer cells, on the other hand, often contain high levels of telomerase, which circumvents the loss of telomeric DNA and endows the cells with unlimited proliferative potential. The goal of Dr. de Lange’s research is to understand how telomeres protect chromosome ends, how telomeres interact with and regulate telomerase, and what happens when telomere function is lost.
The de Lange lab first identified the telomere-specific protein complex, which they named shelterin, and showed that the shelterin complex protects chromosome ends by preventing them from being identified as double-strand breaks. Shelterin is composed of six different proteins, including proteins that bind specifically to the telomere. By removing individual shelterin proteins from the nucleus, Dr. de Lange and her colleagues have found that telomeres are identified as damaged DNA, suggesting that shelterin staves off unnecessary repair. The de Lange lab has also found that telomeres use two distinct shelterin components — POT1 and TRF2 — to independently repress the two main DNA damage signaling pathways — findings that suggest how telomeres induce cell cycle arrest when they become critically shortened.
Without shelterin, the ends of telomeres are mistaken for breaks in the DNA and the ends of chromosomes are inappropriately processed by the two major repair pathways: nonhomologous end-joining and homology-directed repair. The de Lange lab has revealed that when TRF2 is deleted from mouse cells, long trains of joined chromosomes form via the nonhomologous end-joining repair pathway, making cells unable to divide. Using living imaging techniques, the de Lange lab further showed that when the shelterin complex is absent from telomeres, a protein called 53BP1 helps fuse two telomeres by mobilizing their relatively stationary DNA ends.
While end-to-end fusions are detrimental when they occur at telomeres, they are vital for repairing double-stranded breaks when they appear at the middle of the chromosome. By working to understand how cells respond to uncapped telomeres, Dr. de Lange and her colleagues have contributed to the understanding of how cells repair double-stranded breaks, the most lethal and dangerous form of DNA damage.
CAREER
Dr. de Lange earned her undergraduate degree from the University of Amsterdam in 1977, her M.S. from the University of Amsterdam and the National Institute for Medical Research in London in 1981 and her Ph.D. in biochemistry from the University of Amsterdam and the Netherlands Cancer Institute in 1985. From 1985 to 1990 she was a postdoctoral fellow in the laboratory of Nobel laureate Harold Varmus at the University of California, San Francisco, where she was one of the first scientists to isolate the telomeres of human chromosomes. She came to Rockefeller in 1990 as assistant professor and was promoted to associate professor in 1994 and professor in 1997. She was named the Leon Hess Professor in 1999. She is also associate director of the university’s Anderson Center for Cancer Research.
Dr. de Lange is an elected member of the Royal Dutch Academy of Sciences, the New York Academy of Sciences, the European
Molecular Biology Organization, the American Society for Microbiology and the American Academy of Arts and Sciences and a
foreign associate of the National Academy of Sciences. Among numerous awards, she received the National Institutes of Health’s
Director’s Pioneer Award in 2005, the Charlotte Friend Memorial Award from the American Association for Cancer Research in
2004, an honorary degree from Utrecht University in 2003 and the first Paul Marks Prize for Cancer Research in 2001.
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