Heads of Laboratories
Leon Hess Professor
Laboratory of Cell Biology and Genetics
Titia.de.Lange@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. The telomeric repeats wither away in a shortening process that is associated with DNA replication and cell proliferation. Telomerase, the reverse transcriptase that adds TTAGGG repeats to chromosome ends, can counteract this attrition and stabilizes telomeres in the germ line. However, telomerase is absent from most human cells, and as a result, many somatic cells eventually die due to depletion of their telomere reserve. Cancer cells, on the other hand, often reactivate telomerase, thereby achieving unlimited proliferative potential. The goal of Dr. de Lange’s research is to understand how telomeres protect chromosome ends, and what happens when telomere function is lost during the early stages of tumorigenesis before telomerase is activated.
The de Lange lab identified a six subunit protein complex, which they named shelterin, that specifically binds to telomeres. Using Cre-mediated conditional deletion in mouse embryo fibroblasts, Dr. de Lange and her colleagues determined the fate of telomeres lacking one or more of the six shelterin subunits. This work showed that cells lacking shelterin perceive their natural chromosome ends as sites of DNA damage.
Four distinct DNA damage response pathways are activated when telomere protection is lost. When shelterin is compromised, two signaling pathways, initiated by the ATM and ATR DNA damage checkpoint kinases, inappropriately respond to chromosome ends and induce cell cycle arrest. In addition, shelterin represses two DNA double-strand break repair pathways at telomeres, non-homologous end-joining (NHEJ) and homology-directed repair (HDR), which have detrimental outcomes at telomeres.
By deleting individual components of shelterin, the de Lange lab has determined that different shelterin components are dedicated to the repression of distinct pathways. A major mechanistic insight arose from the identification of the t-loop structure of telomeres in which the telomere terminus is sequestered in the double-stranded repeat array of the telomere, thereby hiding the telomere terminus from the DNA damage response. Her group is now working to determine the mechanism by which each shelterin protein inhibits its designated pathway, and how loss of telomere protection contributes to genome instability in human cancer.
CAREER
Dr. de Lange earned 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 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 and is an American Cancer Society Research Professor. She is also associate director of the university’s Anderson Center for Cancer Research.
Among other awards, Dr. de Lange is the recipient of the 2010 AACR Clowes Memorial Award, the 2008 Massachusetts General Hospital Cancer Center Prize, the 2005 NIH Director’s Pioneer Award, the 2004 Charlotte Friend Memorial Award from the AACR and the first Paul Marks Prize for Cancer Research, in 2001. She is an elected member of the Royal Dutch Academy of Sciences, the European Molecular Biology Organization, the American Academy of Arts and Sciences, and a foreign associate of the National Academy of Sciences.
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