Dr. de Lange’s lab focuses on the telomeres in mammalian cells, which are made up of long arrays of double-stranded TTAGGG repeats that end in a single-stranded overhang. This end portion is used by a telomere-specific enzyme, called telomerase, as a base to extend and maintain telomere length. Although telomerase is expressed in the germ line and certain stem cells, it is absent from most other human cells. As each cell division results in a small portion of the telomere being lost, telomere length serves to curb the proliferation of primary human cells. Immortal cancer cells, on the other hand, have stable telomeres due to the activation of telomerase. The goal of the de Lange lab is to understand how telomeres protect chromosome ends, how telomeres interact with telomerase and what happens when telomere function is lost.

The de Lange lab has identified the telomere-specific protein complex, which they called shelterin. Shelterin is composed of six different proteins, including proteins that bind specifically to the double-stranded and single-stranded portions of the telomere. By removing individual shelterin proteins from the cell, Dr. de Lange and her colleagues have found that telomeres activate all aspects of the DNA damage response in response to shelterin impairment. First, damage response factors localize to telomeres, then the p53 pathway induces a cell cycle arrest, and finally the cells undergo senescence or apoptosis. The findings show that the shelterin complex protects chromosome ends by preventing them from being identified and processed as double-strand breaks. The de Lange lab is further dissecting the cellular response to telomere damage, anticipating insights into the mechanism by which shortening telomeres induce apoptosis and senescence.

Shelterin is also required to protect telo-meres from inappropriate DNA repair. When shelterin is inhibited, telomeres become fused by the non-homologous end joining pathway, which is normally used to repair breaks in the DNA. A major insight into how shelterin might block non-homologous end joining came from biochemical and EM experiments that suggested that shelterin remodels telomeric DNA into a looped configuration (the t-loop) in which the 3' end of the telomere is tucked into the double-stranded DNA. This t-loop appears to provide an architectural solution to the problem of chromosome ends.

In some cases, cells continue to prosper even without telomeres. After deleting the shelterin complex in mouse liver cells, which only divide if the organ is injured, the de Lange lab at first saw the expected DNA damage response, but the cells didn’t die. When they injured the organ, however, the cell behaved unexpectedly: although the cell duplicated their DNA as they normally would, they did not divide and simply became larger. Further research in Dr. de Lange’s lab will be examining this process in more detail and investigating whether it applies to different cell types.

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 to 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, the American Academy of Arts and Sciences, and 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 the University of Utrecht in 2003, and the first Paul Marks Prize for Cancer Research in 2001.